(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(19) World Intellectual Property Organization
International Bureau
(43) International Publication Date
25 May 2001 (25.05.2001)
II
PCT
II
(10) International Publication Number
WO 01/36403 Al
(51) International Patent Classification 7 : C07D 295/08,
A61P 29/00, C07D 213/73, 295/12, 213/63
(21) International Application Number: PCT/US00/31582
(22) International Filing Date:
16 November 2000 (16.11.2000)
(25) Filing Language: English
(26) Publication Language: English
(30) Priority Data:
60/165,903 16 November 1999 (16.11.1999) US
(71) Applicant (for all designated States except US):
BOEHRINGER INGELHEIM PHARMACEUTI-
CALS, INC. [US/US]; 900 Ridgebury Road, Ridgefield,
CT 06877 (US).
(72) Inventors; and
(75) Inventors/Applicants (for US only): BREITFELDER,
Steffen [DE/US]; 93 Park Avenue, #1305, Danbury, CT
06810 (US). CIRILLO, Pier, F. [IT/US]; 180 Washington
Road, Woodbury, CT 06798 (US). HAO, Ming-Hong
[US/US]; 11 Scodon Drive, Ridgefield, CT 06877 (US).
HICKEY, Eugene, R. [US/US]; 5 Woodbury Drive,
Danbury, CT 06811 (US). SHARMA, Rajiv [IN/US];
37 Midrocks Road, Ridgefield, CT 06877 (US). SUN,
Sanxing [CN/US]; 38 Padanaram Avenue, 21B, Danbury,
CT 06811 (US). TAKAHASHI, Hidenori [JP/US]; 68
Ehmer Drive, LaGrangeville, NY 12540 (US).
(74) Agents: RAYMOND, Robert et al.; Boehringer Ingel-
heim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box
368, Ridgefield, CT 06877 (US).
(81) Designated States (national): AE, AU, BG, BR, BY, CA,
CN, CZ, EE, HR, HU, ID, IL, IN, JP, KR, KZ, LT, LV, MX,
NO, NZ, PL, RO, RU, SG, SI, SK, TR, UA, US, UZ, VN,
YU, ZA.
(84) Designated States (regional): European patent (AT, BE,
CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC,
NL, PT, SE, TR).
Published:
— With international search report,
— Before the expiration of the time limit for amending the
claims and to be republished in the event of receipt of
amendments.
For two-letter codes and other abbreviations, refer to the "Guid-
ance Notes on Codes and Abbreviations" appearing at the begin-
ning of each regular issue of the PCT Gazette.
<
(54) Title: UREA DERIVATIVES AS ANTI-INFLAMMATORY AGENTS
O
x
>^ -Ar — L
H H
0)
(57) Abstract: Disclosed are novel aromatic compounds of formula (I)
wherein G, X, Ar, L and Q are defined herein. The compounds are use-
ful in pharmaceutic compositions for treating diseases or pathological
conditions involving inflammation such as chronic inflammatory dis-
eases. Also disclosed are processes of making such compounds. The
compounds (I) inhibit cytokine production.
WO 01/36403
PCT/US00/31582
UREA DERIVATIVES AS ANTI - INFLAMMATORY AGENTS
RELATED APPLICATION DATA
This application claims benefit to US provisional application no. 60/165,903 filed
11/16/1999.
TECHNICAL FIELD OF THE INVENTION
This invention relates to novel compounds of formula(I):
wherein G,X,Ar,L and Q of formula(I) are defined below. The compounds of the
invention inhibit production of cytokines involved in inflammatory processes and are
thus useful for treating diseases and pathological conditions involving inflammation such
as chronic inflammatory disease. This invention also relates to processes for preparing
these compounds and to pharmaceutical compositions comprising these compounds.
BACKGROUND OF THE INVENTION
Tumor necrosis factor (TNF) and interleukin-1 (IL-1) are important biological entities
collectively referred to as proinflammatory cytokines. These, along with several other
related molecules, mediate the inflammatory response associated with the immunological
recognition of infectious agents. The inflammatory response plays an important role in
limiting and controlling pathogenic infections.
WO 01/36403
PCT/US00/31582
Elevated levels of proinflammatory cytokines are also associated with a number of
diseases of autoimmunity such as toxic shock syndrome, rheumatoid arthritis,
osteoarthritis, diabetes and inflammatory bowel disease (Dinarello, C.A., et al, 1984,
Rev. Infect. Disease 6:5\). In these diseases, chronic elevation of inflammation
5 exacerbates or causes much of the pathophysiology observed. For example, rheumatoid
synovial tissue becomes invaded with inflammatory cells that result in destruction to
cartilage and bone (Koch, A.E., et al. y 1995, J. Invest. Med. 43: 28-38). An important
and accepted therapeutic approach for potential drug intervention in these diseases is the
reduction of proinflammatory cytokines such as TNF (also referred to in its secreted cell-
10 free form as TNF a) and IL-ip. A number of anti-cytokine therapies are currently in
clinical trials. Efficacy has been demonstrated with a monoclonal antibody directed
against TNFa in a number of autoimmune diseases (Heath, P., "CDP571: An Engineered
Human IgG4 Anti-TNFa Antibody" IBC Meeting on Cytokine Antagonists,
Philadelphia, PA, April 24-5, 1997). These include the treatment of rheumatoid arthritis,
15 Crohn's disease and ulcerative colitis (Rankin, E.C.C., et al., 1997, British J. Rheum. 35:
334-342 and Stack, W.A., et al 9 1997, Lancet 349: 521-524). The monoclonal antibody
is thought to function by binding to both soluble TNFa and to membrane bound TNF.
A soluble TNFa receptor has been engineered that interacts with TNFa. The approach is
20 similar to that described above for the monoclonal antibodies directed against TNFa;
both agents bind to soluble TNFa, thus reducing its concentration. One version of this
construct, called Enbrel (Immunex, Seattle, WA) recently demonstrated efficacy in a
Phase III clinical trial for the treatment of rheumatoid arthritis (Brower et al., 1997,
Nature Biotechnology 15: 1240). Another version of the TNFa receptor, Ro 45-2081
25 (Hoffman-LaRoche Inc., Nutley, NJ) has demonstrated efficacy in various animal models
of allergic lung inflammation and acute lung injury. Ro 45-2081 is a recombinant
chimeric molecule constructed from the soluble 55 kDa human TNF receptor fused to the
hinge region of the heavy chain IgGl gene and expressed in eukaryotic cells (Renzetti, et
al, 1997 \Inflamm. Res. 46: S143).
30
2
WO 01/36403
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IL-1 has been implicated as an immunological effector molecule in a large number of
disease processes. IL-1 receptor antagonist (IL-lra) had been examined in human
clinical trials. Efficacy has been demonstrated for the treatment of rheumatoid arthritis
(Antril, Amgen). In a phase III human clinical trial IL-lra reduced the mortality rate in
5 patients with septic shock syndrome (Dinarello, 1995, Nutrution 11, 492). Osteoarthritis
is a slow progressive disease characterized by destruction of the articular cartilage. IL-1
is detected in synovial fluid and in the cartilage matrix of osteoarthritic joints.
Antagonists of IL- 1 have been shown to diminish the degradation of cartilage matrix
components in a variety of experimental models of arthritis (Chevalier, 1997, Biomed
10 Pharmacother. 51, 58). Nitric oxide (NO) is a mediator of cardiovascular homeostasis,
neurotransmission and immune function; recently it has been shown to have important
effects in the modulation of bone remodeling. Cytokines such as IL-1 and TNF are
potent stimulators of NO production. NO is an important regulatory molecule in bone
with effects on cells of the osteoblast and osteoclast lineage (Evans, et aL, 1996, J Bone
15 Miner Res. 11, 300). The promotion of beta-cell destruction leading to insulin dependent
diabetes mellitus shows dependence on IL-1. Some of this damage may be mediated
through other effectors such as prostaglandins and thromboxanes. IL-1 can effect this
process by controlling the level of both cyclooxygenase II and inducible nitric oxide
synthetase expression (McDaniel et aL, 1996, Proc Soc Exp Biol Med. 211, 24).
20
Inhibitors of cytokine production are expected to block inducible cyclooxygenase (COX-
2) expression. COX-2 expression has been shown to be increased by cytokines and it is
believed to be the isoform of cyclooxygenase responsible for inflammation (M.K.
O'Banion etal., Proc. Natl. Acad. Sci.U.S.A, 1992, 89, 4888.) Accordingly, inhibitors of
25 cytokines such as IL-1 would be expected to exhibit efficacy against those disorders
currently treated with COX inhibitors such as the familiar NSAIDs. These disorders
include acute and chronic pain as well as symptoms of inflammation and cardiovascular
disease.
30 Elevation of several cytokines have been demonstrated during active inflammatory bowel
disease (IBD). A mucosal imbalance of intestinal IL-1 and IL-lra is present in patients
3
WO 01/36403
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with IBD. Insufficient production of endogenous IL-lra may contribute to the
pathogenesis of IBD (Cominelli, et aL, 1996, Aliment Pharmacol Ther. 10, 49).
Alzheimer disease is characterized by the presence of beta-amyloid protein deposits,
neurofibrillary tangles and cholinergic dysfunction throughout the hippocampal region.
5 The structural and metabolic damage found in Alzheimer disease is possibly due to a
sustained elevation of IL-1 (Holden, et aL, 1995, Med Hypotheses, 45, 559). A role for
IL-1 in the pathogenesis of human immunodeficiency virus (HIV) has been identified.
IL-lra showed a clear relationship to acute inflammatory events as well as to the different
disease stages in the pathophysiology of HIV infection (Kreuzer, et aL, 1997, Clin Exp
10 Immunol. 109, 54). IL-1 and TNF are both involved in periodontal disease. The
destructive process associated with periodontal disease may be due to a disregulation of
both IL-1 and TNF (Howells, 1995, Oral Dis. 1, 266).
Proinflammatory cytokines such as TNFa and IL- 1 P are also important mediators of
15 septic shock and associated cardiopulmonary dysfunction, acute respiratory distress
syndrome (ARDS) and multiple organ failure. TNFa has also been implicated in
cachexia and muscle degradation, associated with HIV infection (Lahdiverta et aL, 1988,
Amer. J. Med., 85, 289). Obesity is associated with an increase incidence of infection,
diabetes and cardiovascular disease. Abnormalities in TNFa expression have been noted
20 for each of the above conditions (Loffreda, et aL, 1998, FASEB J. 12, 57). It has been
proposed that elevated levels of TNFa are involved in other eating related disorders such
as anorexia and bulimia nervosa. Pathophysiological parallels are drawn between
anorexia nervosa and cancer cachexia (Holden, et aL, 1996, Med Hypotheses 47, 423).
An inhibitor of TNFa production, HU-2 1 1 , was shown to improve the outcome of closed
25 brain injury in an experimental model (Shohami, et aL, 1997, J NeuroimmunoL 72, 169).
Atherosclerosis is known to have an inflammatory component and cytokines such as IL-1
and TNF have been suggested to promote the disease. In an animal model an IL- 1
receptor antagonist was shown to inhibit fatty streak formation (Elhage et aL, 1998,
Circulation, 97, 242).
30
4
WO 01/36403
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The abnormal expression of inducible nitric oxide synthetase (iNOS) has been associated
with hypertension in the spontaneously hypertensive rat (Chou et al., 1998, Hypertension,
31, 643). IL-1 has a role in the expression of iNOS and therefore may also have a role in
the pathogenesis of hypertension (Singh et al., 1996, Amer. J. Hypertension, 9, 867).
5
IL-1 has also been shown to induce uveitis in rats which could be inhibited with IL-1
blockers. (Xuan et al., 1998, J. Ocular Pharmacol, and Ther., 14, 31). Cytokines
including IL-1, TNF and GM-CSF have been shown to stimulate proliferation of acute
myelogenous leukemia blasts (Bruserud, 1996, Leukemia Res. 20, 65). IL-1 was shown
10 to be essential for the development of both irritant and allergic contact dermatitis.
Epicutaneous sensitization can be prevented by the administration of an anti- IL-1
monoclonal antibody before epicutaneous application of an allergen (Muller, et al, 1996,
Am J Contact Dermat. 7, 177). Data obtained from IL-1 knock out mice indicates the
critical involvement in fever for this cytokine (Kluger et al., 1998, Clin Exp Pharmacol
15 Physiol. 25, 141). A variety of cytokines including TNF, IL-1, IL-6 and IL-8 initiate the
acute-phase reaction which is stereotyped in fever, malaise, myalgia, headaches, cellular
hypermetabolism and multiple endocrine and enzyme responses (Beisel, 1995, Am J Clin
Nutr. 62, 813). The production of these inflammatory cytokines rapidly follows trauma
or pathogenic organism invasion.
20
Other proinflammatory cytokines have been correlated with a variety of disease states.
IL-8 correlates with influx of neutrophils into sites of inflammation or injury. Blocking
antibodies against IL-8 have demonstrated a role for IL-8 in the neutrophil associated
tissue injury in acute inflammation (Harada et al, 1996, Molecular Medicine Today 2,
25 482). Therefore, an inhibitor of IL-8 production may be useful in the treatment of
diseases mediated predominantly by neutrophils such as stroke and myocardial infarction,
alone or following thrombolytic therapy, thermal injury, adult respiratory distress
syndrome (ARDS), multiple organ injury secondary to trauma, acute glomerulonephritis,
dermatoses with acute inflammatory components, acute purulent meningitis or other
30 central nervous system disorders, hemodialysis, leukopherisis, granulocyte transfusion
associated syndromes, and necrotizing enterocolitis.
5
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Rhinovirus triggers the production of various proinflammatory cytokines, predominantly
IL-8, which results in symptomatic illnesses such as acute rhinitis (Winther et aL, 1998,
AmJRhinol. 12, 17).
5 Other diseases that are effected by IL-8 include myocardial ischemia and reperfusion,
inflammatory bowel disease and many others.
The proinflammatory cytokine IL-6 has been implicated with the acute phase response.
IL-6 is a growth factor in a number in oncological diseases including multiple myeloma
10 and related plasma cell dyscrasias (Treon, et aL, 1998, Current Opinion in Hematology 5:
42). It has also been shown to be an important mediator of inflammation within the
central nervous system. Elevated levels of IL-6 are found in several neurological
disorders including AIDS dementia complex, Alzheimer's disease, multiple sclerosis,
systemic lupus erythematosus, CNS trauma and viral and bacterial meningitis (Gruol, et
15 aL, 1997, Molecular Neurobiology 15: 307). IL-6 also plays a significant role in
osteoporosis. In murine models it has been shown to effect bone resorption and to induce
osteoclast activity (Ershler et aL, 1997, Development and Comparative Immunol. 21:
487). Marked cytokine differences, such as IL-6 levels, exist in vivo between osteoclasts
of normal bone and bone from patients with Paget's disease (Mills, et aL, 1997, Calcif
20 Tissue Int. 61, 16). A number of cytokines have been shown to be involved in cancer
cachexia. The severity of key parameters of cachexia can be reduced by treatment with
anti IL-6 antibodies or with IL-6 receptor antagonists (Strassmann, et aL, 1995, Cytokins
Mol Ther. 1, 107). Several infectious diseases, such as influenza, indicate IL-6 and IFN
alpha as key factors in both symptom formation and in host defense (Hayden, et aL,
25 1 998, J Clin Invest 101, 643). Overexpression of IL-6 has been implicated in the
pathology of a number of diseases including multiple myeloma, rheumatoid arthritis,
Castleman's disease, psoriasis and post-menopausal osteoporosis (Simpson, et aL, 1997,
Protein Set 6, 929). Compounds that interfered with the production of cytokines
including IL-6, and TNF were effective in blocking a passive cutaneous anaphylaxis in
30 mice (Scholz et aL, 1998, J. Med. Chem., 41, 1050).
6
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GM-CSF is another proinflammatory cytokine with relevance to a number of therapeutic
diseases. It influences not only proliferation and differentiation of stem cells but also
regulates several other cells involved in acute and chronic inflammation. Treatment with
GM-CSF has been attempted in a number of disease states including burn-wound healing,
5 skin-graft resolution as well as cytostatic and radiotherapy induced mucositis (Masucci,
1996, Medical Oncology 13: 149). GM-CSF also appears to play a role in the replication
of human immunodeficiency virus (HIV) in cells of macrophage lineage with relevance
to AIDS therapy (Crowe et al., 1997, Journal of Leukocyte Biology 62, 41). Bronchial
asthma is characterised by an inflammatory process in lungs. Involved cytokines include
10 GM-CSF amongst others (Lee, 1 998, J R Coll Physicians Lond 32, 56).
Interferon y (IFN y) has been implicated in a number of diseases. It has been associated
with increased collagen deposition that is a central histopathological feature of graft-
versus-host disease (Parkman, 1998, Curr Opin HematoL 5, 22). Following kidney
15 transplantation, a patient was diagnosed with acute myelogenous leukemia.
Retrospective analysis of peripheral blood cytokines revealed elevated levels of GM-CSF
and IFN y. These elevated levels coincided with a rise in peripheral blood white cell
count (Burke, et al, 1995, Leuk Lymphoma, 19, 173). The development of insulin-
dependent diabetes (Type 1) can be correlated with the accumulation in pancreatic islet
20 cells of T-cells producing IFN y (Ablumunits, et al, 1998, JAutoimmun. 11 9 73). IFN y
along with TNF, IL-2 and IL-6 lead to the activation of most peripheral T-cells prior to
the development of lesions in the central nervous system for diseases such as multiple
sclerosis (MS) and AIDS dementia complex (Martino et al., 1998, Ann Neurol 43, 340).
Atherosclerotic lesions result in arterial disease that can lead to cardiac and cerebral
25 infarction. Many activated immune cells are present in these lesions, mainly T-cells and
macrophages. These cells produce large amounts of proinflammatory cytokines such as
TNF, IL-1 and IFN y. These cytokines are thought to be involved in promoting apoptosis
or programmed cell death of the surrounding vascular smooth muscle cells resulting in
the atherosclerotic lesions (Geng, 1997, Heart Vessels Suppl 12, 76). Allergic subjects
30 produce mRNA specific for IFN y following challenge with Vespula venom (Bonay, et
al, 1997, Clin Exp Immunol 109, 342). The expression of a number of cytokines,
7
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including IFN y has been shown to increase following a delayed type hypersensitivity
reaction thus indicating a role for IFN y in atopic dermatitis (Szepietowski, et aL, 1997,
Br J Dermatol 137, 195). Histopathologic and immunohistologic studies were
performed in cases of fatal cerebral malaria. Evidence for elevated IFN y amongst other
5 cytokines was observed indicating a role in this disease (Udomsangpetch et aL, 1997, Am
J Trop Med Hyg. 57, 501). The importance of free radical species in the pathogenesis of
various infectious diseases has been established. The nitric oxide synthesis pathway is
activated in response to infection with certain viruses via the induction of
proinflammatory cytokines such as IFN y (Akaike, et aL, 1998, Proc Soc Exp Biol Med.
10 217, 64). Patients, chronically infected with hepatitis B virus (HBV) can develop
cirrhosis and hepatocellular carcinoma. Viral gene expression and replication in HBV
transgenic mice can be suppressed by a post-transcriptional mechanism mediated by IFN
y, TNF and IL-2 (Chisari, et aL, 1995, Springer Semin Immunopathol. 17, 261). IFN y
can selectively inhibit cytokine induced bone resorption. It appears to do this via the
15 intermediacy of nitric oxide (NO) which is an important regulatory molecule in bone
remodeling. NO may be involved as a mediator of bone disease for such diseases as: the
rheumatoid arthritis, tumor associated osteolysis and postmenopausal osteoporosis
(Evans, et aL, 1996, J Bone Miner Res. 11, 300). Studies with gene deficient mice have
demonstrated that the IL-12 dependent production of IFN y is critical in the control of
20 early parasitic growth. Although this process is independent of nitric oxide the control of
chronic infection does appear to be NO dependent (Alexander et aL, 1997, Philos Trans
R Soc Lond B Biol Sci 352, 1355). NO is an important vasodilator and convincing
evidence exists for its role in cardiovascular shock (Kilbourn, et aL, 1997, Dis Mon. 43,
277). IFN y is required for progression of chronic intestinal inflammation in such
25 diseases as Crohn's disease and inflammatory bowel disease (IBD) presumably through
the intermediacy of CD4+ lymphocytes probably of the TH1 phenotype (Sartor 1996,
Aliment Pharmacol Then 10 Suppl 2, 43). An elevated level of serum IgE is associated
with various atopic diseases such as bronchial asthma and atopic dermatitis. The level of
IFN y was negatively correlated with serum IgE suggesting a role for IFN y in atopic
30 patients (Teramoto et aL, 1998, Clin Exp Allergy 28, 74).
8
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Compounds which modulate release of one or more of the aforementioned inflammatory
cytokines can be useful in treating diseases associated with release of these cytokines. For
example, WO 98/52558 discloses heteroaryl urea compounds which are indicated to be
useful in treating cytokine mediated diseases. WO 99/23091 discloses another class of
5 urea compounds which are useful as anti-inflammatory agents.
U.S. Pat. No. 5,162,360 discloses N-substituted aryl-N'-heterocyclic substituted urea
compounds which are described as being useful for treating hypercholesterolemia and
atheroclerosis.
v
1 0 The work cited above supports the principle that inhibition of cytokine production will be
beneficial in the treatment of various disease states. Some protein therapeutics are in late
development or have been approved for use in particular diseases. Protein therapeutics
are costly to produce and have bioavailability and stability problems. Therefore a need
exists for new small molecule inhibitors of cytokine production with optimized efficacy,
15 pharmacokinetic and safety profiles.
BRIEF St JMMARYOF THE INVENTION
The work cited above supports the principle that inhibition of cytokine production will be
20 beneficial in the treatment of various disease states.
It is therefore an object of the invention to provide novel compounds which inhibit the
release of inflammatory cytokines such as interleukin-1 and tumor necrosis factor.
25 It is a further object of the invention to provide methods for treating diseases and
pathological conditions involving inflammation such as chronic inflammatory disease,
using the novel compounds of the invention.
It is yet a further object of the invention to provide processes of preparation of the above-
30 mentioned novel compounds.
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DETAILED PES CR TPTTON OF THE INVENTION
In one embodiment of the invention there are provided compounds of the formula (I):
X
N N
I I
H H
(I)
wherein:
G is:
an aromatic Ce-io carbocycle or a nonaromatic C3_iocarbocycle saturated or unsaturated;
a 6-10 membered heteroaryl containing 1 or more heteroatoms chosen from O, N and S;
or
a 5-8 membered monocyclic heterocycle or a 8-1 1 membered bicyclic heterocycle, each
containing one or more heteroatoms chosen from O, N and S;
wherein G is substituted by one or more Ri, R2 or R3;
Ar is:
phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl,
dihydrobenzofuranyl, dihydrobenzothienyl, indolenyl, benzothiophenyl,
tetrahydroisoquinolinyl, benzimidazolyl, benzofuranyl, indanyl, indenyl or indolyl each
optionally substituted by one or more R4 or R 5 groups;
L is a:
Ci-10 saturated or unsaturated branched or unbranched carbon chain;
wherein one or more methylene groups are optionally independently replaced by
heteroatoms chosen from O, N and S(0) m ; and
wherein said L is optionally substituted with 0-2 oxo groups and one or more Ci_4
branched or unbranched alkyl optinally substituted by one or more halogen atoms;
10
WO 01/36403
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Qis:
phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, benzimidazolyl,
furanyl, thienyl, pyranyl, naphthyridinyl, pyrazinyl, pyrazolyl, triazolyl, tetrazolyl,
pyrazolo[3,4-b]pyrimidinyl, purinyl, pyrrolo[2,3-b]pyridinyl, pyrazolo[3,4-b]pyridinyl,
tubercidinyl, oxazo[4,5-6]pyridinyl and imidazo[4,5-6]pyridinyl, which are optionally
substituted with one to three Ci_6 alkyl, C\.6 alkoxy, hydroxy, amino, mono- or di-(Ci_3
alkyl)amino, mono- or di-(phenyl-Ci_3 alkyl)amino, Ci-6 alkyl-S(0) m? phenyl- Ci_3-alkoxy
or phenylamino wherein the phenyl ring is optionally substituted with one to two
halogen, Ci_6 alkyl or Ci_6 alkoxy;
tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxanyl,
morpholino, thiomorpholino, thiomorpholino sulfoxide, thiomorpholino sulfone,
piperazinyl, piperidinyl, piperidinonyl, tetrahydropyrimidonyl, cyclohexanone,
cyclohexanol, pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene
sulfone, tetramethylene sulfide, tetramethylene sulfoxide or tetramethylene sulfone which
are optionally substituted with one to three Ci_6 alkyl, Ci_6 alkoxy, hydroxy, mono- or di-
(C1-3 alkyl)amino-Ci_3 alkyl, phenylamino-Ci_ 3 alkyl or C1.3 alkoxy-Ci_ 3 alkyl;
Ci_6 alkoxy, secondary or tertiary amine wherein the amino nitrogen is covalently
bonded to C1.3 alkyl or C1-5 alkoxyalkyl, phenylamino, wherein the phenyl ring is
optionally substituted with one to two halogen, Cue alkoxy, hydroxy or mono- or di-(Ci.3
alkyl)amino, Ci_6 alkyl-S(0) m or phenyl-S(0) m wherein the phenyl ring is optionally
substituted with one to two halogen, Cue alkoxy, hydroxy or mono- or di-(Ci_3
alkyl)amino;
each Ri is independently:
C3-10 branched or unbranched alkyl optionally partially or fully halogenated, and
optionally substituted with one to three C 3 .i 0 cycloalkyl, hydroxy, phenyl, naphthyl ,
11
WO 01/36403
PCT/US00/31582
pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl,
furyl, isoxazolyl or isothiazolyl; each of the aforementioned being optionally substituted
with 1 to 5 halogen, Ci_6 branched or unbranched alkyl which is optionally partially or
fully halogenated, C3-8 cycloalkyl, C 5 _8 cycloalkenyl, hydroxy, cyano, C1-3 alkoxy which
is optionally partially or fully halogenated and NHfeCCO) or mono- or
di(C 1 „3)alkylaminocarbonyl;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl,
bicyclohexanyl or bicycloheptanyl, which are optionally partially or fully halogenated
and optionally substituted with one to three Ci_3 alkyl groups optionally partially or fully
halogenated, cyano, hydroxyCi-3alkyl or aryl; or an analog of cyclopropyl, cyclobutyl,
cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or
bicycloheptanyl wherein one to three ring methylene groups are replaced independently
by O, S(0) m , CHOH, >00, >OS or NH;
C3-10 branched or unbranched alkenyl optionally partially or fully halogenated, and
optionally substituted with one to three Q-5 branched or unbranched alkyl, phenyl,
naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl,
thienyl, furyl, isoxazolyl or isothiazolyl, each of the aforementioned are optionally
substituted with 1 to 5 halogen, C1-6 branched or unbranched alkyl optionally partially or
fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl,
bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, hydroxy, cyano, C1-3 alkoxy
optionally partially or fully halogenated, NHbQO) or mono- or di(Ci_
3)alkylaminocarbonyl; the C3_io branched or unbranched alkenyl is optionally interrupted
by one or more O, N or S(0) m ;
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl,
bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C1.3
alkyl groups;
cyano, halogen;
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WO 01/36403
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methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl;
silyl containing three C1-4 independently branched or unbranched alkyl groups optionally
partially or fully halogenated;
C2-6 branched or unbranched alkyl-C(O), C2-6 branched or unbranched-S, C2-6 branched
5 or unbranched-S(O), C2.6 branched or unbranched- S (0)2;
C2-6 alkynyl branched or unbranched carbon chain optionally partially or fully
halogenated, wherein one or more methylene groups are optionally replaced by O, NH
and S(0) m and wherein said alkynyl group is optionally independently substituted with 0-
10 2 oxo groups, pyrroldinyl, pyrrolyl, one or more Ci_4 branched or unbranched alkyl
optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl,
piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or C 1-4 branched or unbranched
alkylamino optionally substituted by one or more halogen atoms;
15 each R2, R4, and R5 is independently
a C1-6 branched or unbranched alkyl optionally partially or fully halogenated, acetyl,
aroyl, C1-4 branched or unbranched alkoxy optionally partially or fully halogenated,
halogen, methoxycarbonyl or phenylsulfonyl;
20
C1-6 alkoxy, hydroxy, amino, or mono- or di-(Ci_4 alkyl)amino, cyano, halogen;
OR«;
nitro; or
25 mono- or di-(Ci_4 alkyl)amino-S(0)2 optionally partially or fully halogenated, or
H 2 NS0 2 ;
each R3 is independently:
30 hydrogen, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,
pyrrolidinyl, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl,
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oxazolyl, triazolyl, tetrazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl,
benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl,
benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl,
quinazolinyl, pxirinyl or indazolyl wherein each of the aforementioned is optionally
substituted with one to five phenyl, naphthyl, heterocycle or heteroaryl wherein the
heterocyclic and heteraryl moiety is as hereinabove described in this paragraph , Ci_6
branched or unbranched alkyl which is optionally partially or fully halogenated,
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl,
bicyclohexanyl ? bicycloheptanyl, phenyl Ci_ 5 alkyl, naphthyl C1-5 alkyl, halogen, hydroxy,
oxo, cyano, C1.3 alkoxy optionally partially or fully halogenated, phenyloxy,
naphthyloxy, heteraryloxy wherein the heterocyclic moiety is as hereinabove described in
this paragraph, nitro, amino, mono- or di-(Ci_3)alkylamino ? phenylamino, naphthylamino,
heterocyclic or heteroaryl amino wherein the heterocyclic or heteroaryl moiety is as
hereinabove described in this paragraph, NH 2 C(0), a mono- or di-(Ci-3)alkyl
aminocarbonyl, C1.5 alkyl-C(0)-Ci_4 alkyl, amino-Ci.5 alkyl, mono- or di-(Ci_
3 )alkylamino-Ci_ 5 alkyl, amino-S(0) 2) di-(Ci-3)alkylamino-S(0) 2 , R7-C1.5 alkyl, Rg-Q-s
alkoxy, R 9 -C(0)-Ci- 5 alkyl, R10-C1.5 alkyl(Ru)N, carboxy-mono- or di-(Ci_ 5 )-alkyl-
amino;
a fused aryl selected from benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl,
tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heterocycle
selected from cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine,
cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine,
cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline,
cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline,
cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole,
cyclohexanobenzimidazole, cyclopentanobenzoxazole, cyclohexanobenzoxazole,
cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and
cyclohexanothiophene; wherein the fused aryl or fused heterocyclic ring is optionally
independently substituted with 1 to 3 groups selected from phenyl, naphthyl, pyridinyl,
pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl,
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isoxazolyl, isothiazolyl, Ci_6 branched or unbranched alkyl optionally partially or fully
halogenated, halo, cyano, C1-3 alkoxy optionally partially or fully halogenated,
phenyloxy, naphthyloxy, heterocyclicoxy heteroaryloxy wherein the heterocyclic or
heteroaryl moiety is as hereinabove described in this paragraph, nitro, amino, mono- or
5 di-(Ci-3)alkylamino, phenylamino, naphthylamino, heterocyclicamino or heteroarylamino
wherein the heterocyclic or heteroaryl moiety is as hereinabove described in this
paragraph, NH 2 C(0), a mono- or di-(Ci_3)alkyl aminocarbonyl, Ci_ 4 alkyl-OC(O), Ci_ 5
alkyl-C(0)-Ci_4 branched or unbranched alkyl, an amino-Ci-5 alkyl, mono- or di-(Ci_
3 )alkylamino-Ci_5 alkyl, R12-C1-5 alkyl, R13-C1.5 alkoxy, Ri 4 -C(0)-Ci_5 alkyl and Ri 5 -Ci_ 5
10 alkyl(Ri 6 )N;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl,
bicyclohexanyl or bicycloheptanyl optionally partially or fully halogenated and
optionally substituted with one to three Ci_ 3 alkyl groups, or an analog of cyclopropyl,
15 cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl
or bicycloheptanyl wherein one to three ring methylene groups are replaced
independently by O, S(0) m , CHOH, >C=0, >C=S or NH;
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl,
20 bicyclohexenyl or bicycloheptenyl each optionally substituted with one to three C1-3 alkyl
groups;
C1-4 branched or unbranched alkyl-phenyl-C(0)-Co-4 branched or unbranched alkyl, Ci_ 4
branched or unbranched alkyl-C(0)-Co-4 branched or unbranched alkyl, C1-4 branched or
25 unbranched alkyl-phenyl-S(O) m -C 0 -4 branched or unbranched alkyl;
Ci_6 branched or unbranched alkyl or C 1.6 branched or unbranched alkoxy each is
optionally partially or fully halogenated or optionally substituted with R17;
30 Co-6 branched or unbranched alkyl optionally substituted with ORis;
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amino or C1-C5 branched or unbranched mono- or di-alkylamino optionally substituted
with R19;
Cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or cycloheptyloxy which
are optionally partially or fully halogenated and optionally substituted with one to three
C1-3 alkyl groups optionally partially or fully halogenated, wherein one to three ring
methylene groups are replaced independently by O, S(0) m , CHOH, >C=0, >C=S or NH;
R 20 C(O)N(R 21 )-, R22O- or R 23 R 2 4NC(0)-; R 26 (CH 2 ) m C(0)N(R2i)- or
R 26 C(0)(CH 2 ) m N(R2i)s
C2-6alkenyl substituted by R 2 3R24NC(0)-;
C 2 _6 alkynyl branched or unbranched carbon chain optionally partially or fully
halogenated, wherein one or more methylene groups are optionally replaced by O, NH,
S(O), S(0) 2 or S and wherein said alkynyl group is optionally independently substituted
with 0-2 oxo groups, pyrroldinyl, pyrrolyl, one or more Ci_4 branched or unbranched
alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino,
piperidine, piperazine, imidazole, phenyl, pyridine, tetrazole, or Ci_4 branched or
unbranched alkylamino optioanlly substituted by one or more halogen atoms; or
aroyl;
R6 is a:
C1-4 branched or unbranched alkyl optionally partially or fully halogenated and optionally
substituted with R 2 6 ;
each R 7 , Rg, R9, Rio, R12, R13, Ri4, R15, R17, R19, R25 and R 26 is independently:
nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl or
alkylamino mono- or di-Co-4 branched or unbranched optionally partially or fully
halogenated;
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each Ri i and Ri6 is independently:
hydrogen or C1.4 branched or unbranched alkyl optionally partially or fully halogenated;
Ri8 is independently:
hydrogen or a Cm branched or unbranched alkyl optionally independently substituted
with oxo or R25;
R20 is:
Ci_io branched or unbranched alkyl optionally partially or fully halogenated, phenyl or
pyridinyl;
R21 is:
hydrogen or C 1-3 branched or unbranched alkyl optionally partially or fully halogenated;
each R22, R23 and R24 is independently:
hydrogen, Ci_6 branched or unbranched alkyl optionally substituted by carbonylamino-
mono- or di-Ci_3alkyl or amino-mono or diC^alkyl or wherein said Q_6 alkyl optionally
partially or fully halogenated and optionally interrupted by one or more O, N or S,
phenyl, pyridine, mono- or di-Co-4 branched or unbranched alkyl optionally partially or
fully halogenated and alkylamino;
or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring;
m = 0, 1 or 2;
X = O or S; and
the pharmaceutical^ acceptable derivatives thereof.
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In another embodiment of the invention there is provided compounds of the formula(I) as
described immmediately above, and wherein
Gis
phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahy dronaphthyl ,
benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl, benzofuran-3-one, 4H-
benzofl ,4]oxazine-3-one;
pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl,
tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl,
benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl,
dihydrobenzothiophenyl, benzooxazolonyl, benzo[l,4]oxazin-3-onyl, benzodioxolyl,
benzo[l,3]dioxol-2-onyl, tetrahy drobenzopyranyl, indolyl, indolinyl, indolonyl,
indolinonyl, phthalimidyl;
oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl,
morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene
sulfoxidyl, oxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl,
pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl,
thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl,
thioxanyl or dithianyl;
wherein G is substituted by one or more Ri, R2 or R3.
In another embodiment of the invention there is provided compounds of the formula(I) as
described immediately above, and wherein
G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl,
benzimidazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl,
dihydrobenzofuranyl, dihydrobenzothiophenyl, indanyl, indenyl, indolyl, indolinyl,
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indolonyl, indolinonyl, benzofuran-3-one or 4H-benzo[l,4]oxazine-3-one, wherein G is
substituted by one or more Ri, R2 or R3;
Ar is:
5
naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, indanyl, indenyl or indolyl each optionally substituted by one or
more R4 or R5 groups;
10 L is a:
C1-4 saturated or unsaturated branched or unbranched carbon chain;
wherein one or more methylene groups are optionally independently replaced by
heteroatoms chosen from O, N and S(0) m ; and
15 wherein said L is optionally substituted with 0-2 oxo groups and one or more C1-4
branched or unbranched alkyl optionally substituted by one or more halogen atoms;
Qis:
20 phenyl, naphthyl, pyridinyl or imidazolyl which are optionally substituted with one to
three halogen, C1-3 alkyl, C1-3 alkoxy, hydroxy, amino, mono- or di-(Ci_3 alkyl)amino or
mono- or di-(phenyl-Ci_3 alkyl)amino;
tetrahydropyranyl, tetrahydrofuranyl, morpholino, thiomorpholino, thiomorpholino
25 sulfoxide, piperidinyl, piperidinonyl, tetrahydropyrimidonyl, pentamethylene sulfide,
pentamethylene sulfoxide or pentamethylene sulfone which are optionally substituted
with one to three Ci_3 alkyl, C1.3 alkoxy, hydroxy, mono- or di-(Ci_3 alkyl)amino-Ci_3
alkyl, phenylamino-Ci-3 alkyl or C1-3 alkoxy-Ci_3 alkyl;
30 each Ri is independently:
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C3.5 branched or unbranched alkyl optionally partially or fully halogenated, and
optionally substituted with one to three C3-6 cycloalkyl, hydroxy, phenyl, thienyl, furyl,
isoxazolyl or isothiazolyl; each of the aformentioned being optionally substituted with 1
to 5 halogen, C1-3 alkyl which is optionally partially or fully halogenated, hydroxy, cyano
or C i_3 alkoxy optionally partially or fully halogenated;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl
optionally partially or fully halogenated and optionally substituted with one to three C1.3
alkyl groups optionally partially or fully halogenated, CYANO, hydroxyC 1-3 alkyl or
phenyl; or an analog of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl,
bicyclopentanyl or bicyclohexanyl wherein one to three ring methylene groups are
independently replaced by O, S, CHOH, >C=0, >C=S or NH; or
silyl containing three C1-4 independently branched or unbranched alkyl groups optionally
partially or fully halogenated;
each R3 is independently:
hydrogen, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrrolylidinyl, imidazolyl
or pyrazolyl, wherein each of the aforementioned is optionally substituted with one to
five phenyl, naphthyl, heterocycle or heteroaryl as hereinabove described in this
paragraph, C1-6 branched or unbranched alkyl which is optionally partially or fully
halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl,
bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1.5 alkyl, naphthyl Ci_5 alkyl,
halogen, oxo, hydroxy, cyano, C1-3 alkoxy optionally partially or fully halogenated,
phenyloxy, naphthyloxy, heteraryloxy or heteryclicoxy wherein the heteraryl or
heterocyclic moiety is as hereinabove described in this paragraph, nitro, amino, mono- or
di-(Ci-3)alkylamino, phenylamino, naphthylamino, heterocyclic or heteroaryl amino
wherein the heterocyclic or heteroaryl moiety is as hereinabove described in this
paragraph, NH2C(0) ? a mono- or di- (Chalky 1 aminocarbonyl, C1.5 alkyl-C(0)-Ci_4
alkyl, amino-Ci.5 alkyl, mono- or di-(Ci_3)alkylamino-Ci_ 5 alkyl, amino-S(0)2, di-(Ci-
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3 )alkylamino-S(0) 2 , R7-C1.5 alkyl, Rg-Ci-s alkoxy, R 9 -C(0)-Ci_ 5 alkyl, R10-C1-5
alkyl(Rn)N or carboxy-mono- or di-(Ci_5)-alkyl-amino;
C1.3 alkyl or C 1.3 alkoxy optionally partially or fully halogenated or optionally substituted
5 with R17;
Cyclopropyloxy, cyclopentyloxy or cyclohexyloxy which are optionally partially or fully
halogenated and optionally substituted with one to three C1-3 alkyl groups optionally
partially or fully halogenated, wherein one to three ring methylene groups are replaced
independently by O, S(0) m , CHOH, >C=0, >OS or NH;
10 Co-6 branched or unbranched alkyl optionally substituted with ORis;
amino or Q -C5 branched or unbranched mono- or di-alkylamino optionally substituted
with Ri 9 ;
R 2 oC(0)N(R 2 i)-, R22O- ; R 23 R24NC(0)-; R26CH 2 C(0)N(R 2 i)- or R 26 C(0)CH 2 N(R 21 )-;
15
C 2 _4alkenyl substituted by R 23 R24NC(0)-;
C2-4 alkynyl branched or unbranched carbon chain optionally partially or fully
halogenated and optionally independently substituted with 0-2 oxo groups, pyrroldinyl,
20 pyrrolyl or one or more C1-4 branched or unbranched alkyl optionally substituted by one
or more halogen atoms;
Xis O;
and
25 R23 and R24 taken together optionally form imidazole, piperidine, morpholino, piperazine
or a pyridinyl ring.
In yet another embodiment of the invention there is provided compounds of the
30 formula(I) as described immediately above, and wherein:
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G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl,
benzothiophenyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indanyl, indolyl,
indolinyl, indolonyl, indolinonyl, cyclopropanyl, cyclohexanyl, piperidinyl or
tetrahydropyran, wherein G is substituted by one or more Ri, R2 or R 3 ;
Ar is naphthyl;
L is a:
C1-4 alkyl or alkynyl branched or unbranched carbon chain;
wherein one methylene group is optionally independently replaced by
heteroatoms chosen from O, N and S(0) m ; and
wherein said L is optionally substituted with 0-2 oxo groups and one or more C1-2
alkyl optionally substituted by one or more halogen atoms;
Qis:
phenyl, pyridinyl, pyrimidinyl, imidazolyl, tetrahydropyranyl, morpholino,
thiomorpholino, thiomorpholino sulfoxide, piperidinyl, piperidinonyl or pentamethylene
sulfoxide which are optionally substituted with one to three amino, mono- or di-(phenyl-
Ci_ 3 alkyl)amino, methyl, ethyl, methoxy, ethoxy, methoxymethyl or ethoxymethyl;
each Ri is independently:
C3-5 branched or unbranched alkyl optionally partially or fully halogenated, and
optionally substituted with phenyl substituted with 0 to 5 halogen, C1.3 alkyl optionally
partially or fully halogenated, hydroxy, cyano or C^alkoxy optionally partially or fully
halogenated;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl
optionally partially or fully halogenated and optionally substituted with one to three Ci_3
alkyl groups optionally partially or fully halogenated, cyano, hydroxyCi_ 3 alkyl or phenyl;
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or an analog of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or
bicyclohexanyl wherein one ring methylene group is replaced by O; and
silyl containing three C1-2 independently branched or unbranched alkyl groups optionally
partially or fully halogenated;
each R3 is independently:
hydrogen, phenyl , pyridinyl, pyrimidinyl, pyrrolylidinyl, 2,5-pyrrolidin-dione,
imidazolyl, pyrazolyl, each of the aforementioned is optionally substituted with one to
five C1-3 alkyl optionally partially or fully halogenated, halogen, oxo, hydroxy, cyano or
Ci_3 alkoxy optionally partially or fully halogenated;
C1-3 alkyl or C1-3 alkoxy which may optionally be partially or fully halogenated or
optionally substituted with R17;
Cyclopropyloxy, cyclopentyloxy or cyclohexyloxy which are optionally partially or fully
halogenated and optionally substituted with one to three C1-3 alkyl groups optionally
partially or fully halogenated, wherein one to three ring methylene groups are replaced
independently by O, S(0) m , CHOH, >00, >C=S or NH;
C0-3 branched or unbranched alkyl optionally substituted with ORig;
amino or C1-C3 branched or unbranched mono- or di-alkylamino optionally substituted
with R19;
R 20 C(O)N(R 2 i)-, R22O- ; R 23 R24NC(0)-; R 2 6CH 2 C(0)N(R 21 )- or R 26 C(0)CH 2 N(R 2l )-;
C 2 -4 alkenyl substituted by R 2 3R 2 4NC(0)-; or
C 2 _4 alkynyl substituted with pyrroldinyl or pyrrolyl;
and
R23 and R 2 4 taken together optionally form morpholino.
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In yet still another embodiment of the invention there is provided compounds of the
formula(I) as described immediately above, and wherein
G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl,
dihydrobenzofiiranyl, indanyl, indolinyl, indolonyl, indolinonyl or cyclopropanyl,
wherein G is substituted by one or more Ri, R2 or R3;
Ar is 1 -naphthyl;
L is:
O-CH2-, O-CH2CH2, 0-CH 2 CH 2 CH 2 , 0-CH 2 CH 2 (CH 3 ), 0-CH 2 (CH 3 )CH 2 , NHCH 2 ,
NHCH2CH 2) NHCH 2 CH2CH 2 , S(0) m CH 2 , S(0) m CH 2 CH 2 , S(0) m CH 2 CH 2 CH 2 , CH 2 CH 2 ,
CH 2 CH 2 CH 2 , 0-CH 2 C(0),
HC=C— CH 2 or HC=C— CH 2 0
each Ri is independently:
C3.5 branched or unbranched alkyl optionally partially or fully halogenated, and
optionally substituted with phenyl;
cyclopropyl, cyclopentanyl, cyclohexanyl or bicyclopentanyl optionally substituted with
one to three methyl groups optionally be partially or fully halogenated, CYANO,
hydroxymethyl or phenyl;
cyclopentyloxy or cyclohexyloxy which are optionally partially or fully halogenated;
2-tetrahydrofuranyl substituted by methyl; or
trimethylsilyl;
each R3 is independently:
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hydrogen, phenyl, pyridinyl, pyrimidinyl, pyrrolylidinyl, 2,5-pyrrolidin-dione,
imidazolyl or pyrazolyl, wherein each of the aforementioned is optionally substituted
with C1-2 alkyl optionally partially or fully halogenated;
5 C1-3 alkyl or C1-3 alkoxy each optionally partially or fully halogenated or optionally
substituted with diethylamino;
C0-3 branched or unbranched alkyl optionally substituted with ORis;
amino or C1-C3 branched or unbranched mono- or di-alkylamino optionally substituted
10 with Ri 9 ;
CH 3 C(0)NH-, R22O- ; R 23 R24NC(0)-; R 26 CH 2 C(0)N(R 2 i)- or R 26 C(0)CH 2 N(R 21 )s
C 2 _4alkenyl substituted by R 2 3R 2 4NC(0)-; or
15 C 2 _4 alkynyl substituted with pyrroldinyl or pyrrolyl;
R 2 3 and R 2 4 are H or R23 and R 2 4 taken together optionally form morpholino; and
R 2 6 is morpholino.
20
In another embodiment of the invention there is provided of the formula(I) as described
immediately above, and wherein
G is phenyl substituted by one or more Ri, R 2 or R3;
25 and
L is:
O, NH, CH 2 or S(0) m .
30 In yet another embodiment of the invention there is provided of the formula(I) as
described in the fourth embodiment above, and wherein
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G is phenyl or pyridinyl substituted by one or more Ri, R2 or R3;
Ar is 1-naphthyl;
5
L is:
C(0)CH 2 - , >C(0), O, or CH 2 ;
each Ri is independently:
10
C3.5 branched or unbranched alkyl optionally partially or fully halogenated, and
each R3 is independently:
15 hydrogen, Ci_3 alkyl or C 1-3 alkoxy each optionally be partially or fully halogenated or
optionally substituted with diethylamino;
CH 3 C(0)NH-, R22O- ; R 23 R24NC(0)-; R 26 C(0)N(R 2 i)- or R 26 C(0)CH 2 N(R 21 )-;
20 R 2 3 and R 2 4 are H or R 2 3 and R 2 4 taken together optionally form morpholino;
and
R 2 6 is alkylamino mono- or di-Co-4 branched or unbranched.
25 In another embodiment of the invention there is provided of the formula(I) as described
immediately above, and wherein
G is pyridinyl
and
30 L is C(Q)CH 2 - , >C(0) 5 O or CH 2 .
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Any compounds of this invention containing one or more asymmetric carbon atoms may
occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures
and individual diastereomers. All such isomeric forms of these compounds are expressly
included in the present invention. Each stereogenic carbon may be in the R or S
5 configuration, or a combination of configurations.
Some of the compounds of formula (I) can exist in more than one tautomeric form. The
invention includes all such tautomers.
10 All terms as used herein in this specification, unless otherwise stated, shall be understood
in their ordinary meaning as known in the art. For example, "Ci-4alkoxy" is a Ci-4alkyl
with a terminal oxygen, such as methoxy, ethoxy, propoxy, and butoxy. All alkyl, alkenyl
and alkynyl groups shall be understood as being branched or unbranched where
structurally possible and unless otherwise specified. Other more specific definitions are
15 as follows:
The term "aroyl" as used in the present specification shall be understood to mean
"benzoyl" or "naphthoyl".
20 The term "carbocycle" shall be understood to mean an aliphatic hydrocarbon radical
containing from three to twelve carbon atoms. Carbocycles include hydrocarbon rings
containing from three to ten carbon atoms. These carbocycles may be either aromatic or
non-aromatic ring systems. The non-aromatic ring systems may be mono- or
polyunsaturated. Preferred carbocycles include but are not limited to cyclopropyl,
25 cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptanyl,
cycloheptenyl, phenyl, indanyl, indenyl, benzocyclobutanyl, dihydronaphthyl,
tetrahydronaphthyl, naphthyl, decahydronaphthyl, benzocycloheptanyl and
benzocyclohepteny 1 .
30 The term "heterocycle" refers to a stable nonaromatic 4-8 membered (but preferably, 5 or
6 membered) monocyclic or nonaromatic 8-11 membered bicyclic heterocycle radical
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which may be either saturated or unsaturated. Each heterocycle consists of carbon atoms
and one or more, preferably from 1 to 4 heteroatoms chosen from nitrogen, oxygen and
sulfur. The heterocycle may be attached by any atom of the cycle, which results in the
creation of a stable structure. Preferred heterocycles include but are not limited to, for
5 example oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl,
piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl,
tetramethylene sulfoxidyl, oxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl,
homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl,
decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl,
10 oxocanyl, heptacanyl, thioxanyl, dithianyl.
The term "heteroaryl" shall be understood to mean an aromatic 5-8 membered
monocyclic or 8-1 1 membered bicyclic ring containing 1-4 heteroatoms chosen from N,0
and S. Such heteroaryls include: pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl,
15 tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl,
pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl,
benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzooxazolonyl,
benzo[l,4]oxazin-3-onyl, benzodioxolyl, benzo[l,3]dioxol-2-onyl,
tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl, indolinonyl, phthalimidyl.
20
The term "heteroatom" as used herein shall be understood to mean atoms other than
carbon such as O, N, S and P.
The term "aryl" as used herein shall be understood to mean aromatic carbocycle or
25 heteroaryl as defined herein.
Terms which are analogs of the above cyclic moieties such as aryloxy or heteroaryl
amine shall be understood to mean an aryl, heteroaryl, heterocycle as defined above
attached to it's respective group.
30
As used herein, "nitrogen" and "sulfur" include any oxidized form of nitrogen and sulfur
and the quaternized form of any basic nitrogen.
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The term "halogen" as used in the present specification shall be understood to mean
bromine, chlorine, fluorine or iodine.
5 The compounds of the invention are only those which are contemplated to be 'chemically
stable' as will be appreciated by those skilled in the art. For example, a compound which
would have a 'dangling valency', or a 'carbanion' are not compounds contemplated by
the invention.
10 The invention includes pharmaceutically acceptable derivatives of compounds of formula
(I) . A "pharmaceutically acceptable derivative" refers to any pharmaceutically
acceptable salt or ester of a compound of this invention, or any other compound which,
upon administration to a patient, is capable of providing (directly or indirectly) a
compound of this invention, a pharmacologically active metabolite or pharmacologically
15 active residue thereof. A pharmacologically active metabolite shall be understood to
mean any compound of the formula(I) capable of being metabolized enzymatically or
chemically. This includes, for example, hydroxylated or oxidized derivative compounds
of the formula(I).
20 Pharmaceutically acceptable salts of the compounds of this invention include those
derived from pharmaceutically acceptable inorganic and organic acids and bases.
Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric,
fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfuric,
tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfiiric
25 and benzenesulfonic acids. Other acids, such as oxalic acid, while not themselves
pharmaceutically acceptable, may be employed in the preparation of salts useful as
intermediates in obtaining the compounds of this invention and their pharmaceutically
acceptable acid addition salts. Salts derived from appropriate bases include alkali metal
(e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(C^-C4
30 alkyl)4 + salts.
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In addition, the compounds of this invention include prodrugs of compounds of the
formula (I). Prodrugs include those compounds that, upon simple chemical
transformation, are modified to produce compounds of the invention. Simple chemical
transformations include hydrolysis, oxidation and reduction. Specifically, when a
5 prodrug of this invention is administered to a patient, the prodrug may be transformed
into a compound of formula (I), thereby imparting the desired pharmacological effect.
10 METHODS OF USE
In accordance with the invention, there are provided methods of using the compounds of
the formula (I). The compounds of the invention effectively block inflammatory cytokine
15 production from cells. The inhibition of cytokine production is an attractive means for
preventing and treating a variety of disorders associated with excess cytokine production,
e.g., diseases and pathological conditions involving inflammation. Thus, the compounds
of the invention are useful for the treatment of such conditions. These encompass
chronic inflammatory diseases including, but not limited to, osteoarthritis, multiple
20 sclerosis, Guillain-Barre syndrome, Crohn's disease, ulcerative colitis, psoriasis, graft
versus host disease, systemic lupus erythematosus and insulin-dependent diabetes
mellitus. The compounds of the invention can also be used to treat other disorders
associated with the activity of elevated levels of proinflammatory cytokines such as
responses to various infectious agents and a number of diseases of autoimmunity such as
25 rheumatoid arthritis, toxic shock syndrome, diabetes and inflammatory bowel diseases
unrelated to those listed above are discussed in the Background of the Invention.
In addition, the compounds of the invention being inhibitors of cytokine production are
expected to block inducible cyclooxygenase (COX-2) expression. COX-2 expression has
30 been shown to be increased by cytokines and it is believed to be the isoform of
cyclooxygenase responsible for inflammation (M.K. O'Banion et al. 9 Proc. Natl. Acad.
Set U.S.A, 1992, 89, 4888.) Accordingly, the present novel compounds would be
expected to exhibit efficacy against those disorders currently treated with COX inhibitors
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such as the familiar NSAIDs. These disorders include acute and chronic pain as well as
symptoms of inflammation and cardiovascular disease.
As discussed in the Background of the Invention, IL-8 plays a role in the influx of
5 neutrophils into sites of inflammation or injury. Therefore, in a yet further aspect of the
invention, the compounds of the invention may be useful in the treatment of diseases
mediated predominantly by neutrophils such as stroke and myocardial infarction, alone or
following thrombolytic therapy, thermal injury, adult respiratory distress syndrome
(ARDS), multiple organ injury secondary to trauma, acute glomerulonephritis,
10 dermatoses with acute inflammatory components, acute purulent meningitis or other
central nervous system disorders, hemodialysis, leukopherisis, granulocyte transfusion
associated syndromes, and necrotizing entrerocolitis.
For therapeutic use, the compounds of the invention may be administered in any
1 5 conventional dosage form in any conventional manner. Routes of administration include,
but are not limited to, intravenously, intramuscularly, subcutaneously, intrasynovially, by
infusion, sublingually, transdermally, orally, topically or by inhalation. The preferred
modes of administration are oral and intravenous.
20 The compounds of this invention may be administered alone or in combination with
adjuvants that enhance stability of the inhibitors, facilitate administration of pharmaceutic
compositions containing them in certain embodiments, provide increased dissolution or
dispersion, increase inhibitory activity, provide adjunct therapy, and the like, including
other active ingredients. Advantageously, such combination therapies utilize lower
25 dosages of the conventional therapeutics, thus avoiding possible toxicity and adverse side
effects incurred when those agents are used as monotherapies. Compounds of the
invention may be physically combined with the conventional therapeutics or other
adjuvants into a single pharmaceutical composition. Advantageously, the compounds
may then be administered together in a single dosage form. In some embodiments, the
30 pharmaceutical compositions comprising such combinations of compounds contain at
least about 5%, but more preferably at least about 20%, of a compound of formula (I)
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(w/w) or a combination thereof. The optimum percentage (w/w) of a compound of
formula(I) may vary and is within the purview of those skilled in the art. Alternatively,
the compounds may be administered separately (either serially or in parallel). Separate
dosing allows for greater flexibility in the dosing regime.
5
As mentioned above, dosage forms of the compounds of this invention include
pharmaceutically acceptable carriers and adjuvants known to those of ordinary skill in the
art. These carriers and adjuvants include, for example, ion exchangers, alumina,
aluminum stearate, lecithin, serum proteins, buffer substances, water, salts or electrolytes
10 and cellulose-based substances. Preferred dosage forms include, tablet, capsule, caplet,
liquid, solution, suspension, emulsion, lozenges, syrup, reconstitutable powder, granule,
suppository and transdermal patch. Methods for preparing such dosage forms are known
(see, for example, H.C. Ansel and N.G. Popovish, Pharmaceutical Dosage Forms and
Drug Delivery Systems, 5th ed., Lea and Febiger (1990)). Dosage levels and
15 requirements are well-recognized in the art and may be selected by those of ordinary skill
in the art from available methods and techniques suitable for a particular patient. In some
embodiments, dosage levels range from about 1-1000 mg/dose for a 70 kg patient.
Although one dose per day may be sufficient, up to 5 doses per day may be given. For
oral doses, up to 2000 mg/day may be required. As the skilled artisan will appreciate,
20 lower or higher doses may be required depending on particular factors. For instance,
specific dosage and treatment regimens will depend on factors such as the patient's
general health profile, the severity and course of the patient's disorder or disposition
thereto, and the judgment of the treating physician.
In order that this invention be more fully understood, the following examples are set
25 forth. These examples are for the purpose of illustrating preferred embodiments of this
invention, and are not to be construed as limiting the scope of the invention in any way.
The examples which follow are illustrative and, as recognized by one skilled in the art,
particular reagents or conditions could be modified as needed for individual compounds.
30 Starting materials used in the scheme below are either commercially available or easily
prepared from commercially available materials by those skilled in the art.
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GENERAL SYNTHETIC METHODS
The invention additionally provides for methods of making the compounds of the formula
(I). In all schemes "G" in the formulas shown below shall have the meaning of "G" in the
formula (I) of the invention desrcibed hereinabove.
The compounds of the invention may be prepared by Method A, B, C or D as illustrated
in Scheme I, preferably method C.
Scheme I
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Method A
**NH.
Ila
OCN-Ar-L-Q
III
O
G ^N- Ar - L - Q
i i
H H
I (or a precursor of I)
Method B
NH.
Ila
1 . phosgene
2. H 2 N-Ar-L-Q
IV
o
G s- l V Ar - | - Q
I I
H H
I (or a precursor of I)
Method C
NH.
Ila
CICCXPh
O
G. N A Q .Ph
i
H
IV
o
G ^ N ^N' Ar " L - Q
i i
H H
I (or a precursor of I)
Method D
COOH
lib
1 . ethyl chloroformate
2. sodium azide
3. heat
NCO
Va
IV
O
G ^N-V Ar - L - Q
I I
H H
I (or a precursor of I)
In Method A, a mixture of an arylamine of formula Ila and an arylisocyanate of formula
III is dissolved in a non-protic, anhydrous solvent such as THF, ether, toluene, dioxane or
ethyl acetate. The preferred solvent is THF. The mixture is stirred at between 0 - 45° C,
preferably at 25° C, for 2-24 h, and the volatiles are removed. Purification of the residue
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can be accomplished by recrystallization from an appropriate solvent such as ethyl
acetate/hexanes, ethyl acetate/methanol, THF/petroleum ether or ethanol/water or by
silica gel chromatography, using for example, hexanes and ethyl acetate as eluents,
providing the product of formula I or precursors thereof.
In Method B, an arylamine of formula Ha is dissolved in a halogenated solvent, such as
methylene chloride, chloroform or dichloroethane. The preferred solvent is methylene
chloride. The mixture is diluted with aqueous alkali, such as sodium bicarbonate or
potassium carbonate, cooled in an ice bath and phosgene is added. The mixture is
vigorously stirred for 5-30 min, with 10 min being preferable. The organic layer is
dried, with agents such as MgS0 4 or Na 2 S0 4 , and the volatiles removed to provide the
corresponding isocyanate. The isocyanate and arylamine IV are mixed in a non-protic,
anhydrous solvent such as THF, ether, toluene, dioxane, methylene chloride or ethyl
acetate. The preferred solvent is THF. The mixture is stirred at between 0 - 45° C,
preferably at 25° C, for 2 - 24 h, and the volatiles are removed. Purification of the residue
by recrystallization or by silica gel chromatography, as above, provides the product of
formula I or precursors thereof.
In Method C, an arylamine of formula Ha is dissolved in a suitable halogenated solvent
such as methylene chloride, chloroform or dichloroethane. The preferred solvent is
methylene chloride. A suitable base such as triethylamine may be added, followed by an
alkyl or aryl chloroformate, such as /-butyl chloroformate or phenyl chloroformate
(shown). The mixture is stirred at between 0 - 85° C, preferably at reflux temperature, for
2 - 24 h, and the volatiles are removed providing carbamate V. The carbamate and
arylamine IV are mixed in a non-protic, anhydrous solvent such as THF, ether, toluene,
dioxane, methylene chloride or ethyl acetate. The preferred solvent is THF. The mixture
is stirred at between 0 - 1 10 °C, preferably at reflux temperature, for 2 - 24 h, and the
volatiles are removed. Purification of the residue as above provides the product of
formula I or precursors thereof.
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In Method D, an aromatic carboxylic acid is dissolved in a non-protic solvent, such as
THF or diethyl ether, and an inorganic base, such as triethyl amine is added and the
mixture is cooled to -30-0°C, with the preferred temperature being -10°C. An alkyl
chloroformate, such as ethyl chloroformate, is added dropwise and the resulting mixture
5 stirred at below room temperature, such as 0°C for 1-3 hours. A solution of sodium azide
in water is added and the mixtiure stirred between 1-3 hours, diluted with toluene and the
organic layer dried and reduced in volume. This mixture is heated at reflux for 1-4 hours,
cooled to room temperature to give isocyanate (Vb) which can be reacted with amine
(IV) to give product of formula I or precursors thereof.
10
Method E describes a procedure by which one may obtain a product of formula (I) in
which Ar is tetrahydroquinoline. Preparations of tetrahydroquinoline intermediates that
may be used are known in the art (see for example C. Wang et al., Biorg. Med. Chem.
Lett, 1998, 2685; W.S. Johnson and B. G. Buell, J. Am. Chem. Soc., 1952, 74, 4513;
15 P.D. Leeson et al., Med. Chem. Res., 1991, 7, 64; A.L. Tokes, Synth. Commun., 1989, 19,
2081; U. Gerlach et al., EP 0 857 724 Al, 05/02/1998). The following method is
illustrative.
Aniline is reacted with an acrylate ester such as t-butyl acrylate, in a suitable solvent such
20 as acetic acid at reflux temperature. The product obtained is cyclized by heating under
acidic conditions, such as heating in polyphosphoric acid to give the cyclic ketone. The
ketone is reduced with a suitable reducing agent such as NaBH4 to give the
corresponding alcohol. The alcohol is converted to the amine by methods known in the
art, for example, reaction with sodium azide under anhydrous acidic conditions in
25 ethereal solvent provides the azide. Protection of the tetrahydroquinoline nitrogen, for
example by treatment with t-butyl dicarbonate under heating conditions affords the *-boc
protected compound. Reaction under suitable reducing conditions, for example,
Pd/charcoal and H 2 gas affords the /-boc protected 4-amino tetrahydroquinoline.
30 This may then be reacted using the desired Method B, C or D, to provide the urea.
Deprotection, for example with trifluoroacetic acid, can be followed by further reaction to
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add L-Q to provide the desired product of formula (I). For example, treatment with the
desired acid, such as 4-pyridine acetic acid hydrochloride in the presence of a suitable
carbodiimide coupling reagent provides an amide. Reaction with an arylaldehyde, for
example 3,5-dimethoxybenzaldehyde in the presence of a suitable reducing agent such as
Na(AcO)3BH at room temperature affords the tetrahydroquinoline product in which L is a
methylene bridge and Q is a substituted aryl group.
Method E
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RXPERIMENTAL SECTION
Arylamine intermediates of formula Ha are either commercially available or may be
prepared by methods known to those skilled in the art. Examples 1-5 (Methods F-J) are
representative of procedures for preparing aryl amine or aryl isocyanate derivatives that
may be used in Methods A-D. It will be obvious to those skilled in the art that other
desired intermediates could be made by these methods by using appropriately substituted
starting materials and intermediates.
Example 1 (Method F): Synthesis of 5-terf-butyl-2-methylaniline
To a solution of 4-ter/-butyl toluene (5 g ? 33.7 mmol) in acetonitrile (150 mL) at 0°C was
added nitronium tetrafluoroborate (5.83 g, 40.5 mmol). After 30 min at room
temperature, the reaction was diluted with water (50 mL) and extracted with ethyl acetate
(3x30 mL). The combined organic extracts were washed with brine and dried (MgS0 4 ),
Removal of the volatiles in vacuo left a residue which was purified by flash
chromatography using 10 % methylene chloride in petroleum ether as eluent.
Concentration in vacuo of the product rich fractions provided 3.8 g of 4-ter*-butyl-2-
nitro toluene.
4-ter/-Butyl-2-nitrotoluene (200 mg, 1.1 mmol) was dissolved in DMF (10 mL). The
catalyst (10% Pd/C, 5 mg) was added and the system was purged with argon then
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exposed to H2 (1 atm) for 12 h. The mixture was filtered over a pad of diatomaceous
earth and the filtrate was diluted with water and extracted with ethyl acetate (3x10 mL).
The combined organic extracts were washed with brine and dried (MgSC>4). Removal of
the volatiles in vacuo provided the product 5-terr-bu1yl-2-methylaniline.
Example 2 (Method G): Synthesis of 6-tert-butyl-2-chloro-3-methylpyridin-yl-
isocyanate
A mixture of 2-*-butyl-6-chloro-5-methylpyridine-4-carboxylic acid methyl ester (2.27 g,
9.39 mmol) and LiOH monohydrate (2.36 g, 56.3 mmol) in methanol (30 mL) and water
(10 mL) was stirred at room temperature for 24 h. Removal of the volatiles in vacuo
provided a residue which was purified by chromatography on silica gel using 5 % TFA in
dichloromethane as the eluent. Concentration in vacuo of the product rich fractions
provided the corresponding carboxylic acid (1.41 g, 66.3 %).
To a stirred solution of the above carboxylic acid (0.54 g, 2.36 mmol) and triethylamine
(0.66 mL, 4.75 mmol) in THF (6 mL) at -10 °C ethyl chloroformate (0.34 mL, 3.51
mmol) was added dropwise. The resulting mixture was stirred at 0 °C for 1 h. A solution
of sodium azide (0.40 g, 6.0 mmol) in water (2 mL) was added and stirring was continued
for another 1 h. The mixture was extracted with toluene. The organic phase was
separated, dried with sodium sulfate, and reduced in volume to 1 5 mL and heated at
reflux for 2 h to provide 6-tert-butyl-2-chloro-3-methylpyridin-yl-isocyanate which was
used without further purification.
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Example 3 (Method H): Synthesis of 5-tert-butyl-2-(lH-pyrazol-4-yl)aniline
Methyl 4-^-butylphenylacetate (20 mmol) was dissolved in MeOH (160 mL) and treated
with water (40 mL) and LiOH monohydrate (30 mmol). The reaction was allowed to stir
at room temperature overnight. The volatiles were removed under reduced pressure and
the remaining residue was diluted with water and neutralized to pH 4 with 1 N sulfuric
acid. The resulting solids were filtered, washed with water and dried to leave 4-t-
butylphenylacetic acid as an off-white solid (3.8 g 5 99%).
Anhydrous DMF (139 mmol) was cooled to 0°C and treated with POCI3 (79.6 mmol).
After 5 min, 4-/-butylphenylacetic acid (19.9 mmol) was added and the mixture heated at
1 10°C for 2 h, cooled to room temperature and poured into a stirred solution of NaPFe
(19.8 mmol) in water (200 mL). The solid was filtered, washed with water, and dried (7.8
g, 97%).
A mixture of the above salt (5 mmol) and hydrazine hydrate (5 mmol) in EtOH (50 mL)
was heated at 90°C for 2 h and cooled to room temperature. The volatiles were removed
under reduced pressure and the remaining residue diluted with ice water. The solids were
filtered, washed with water and dried providing 4-(4-*-butylphenyl)pyrazole (973 mg,
97%).
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To a mixture of 4-(4-*-butylphenyl)pyrazole (0.5 mmol) in MeCN (2 mL) at 0°C was
added NO2BF4 (0.6 mmol). The mixture was allowed to warm slowly to room
temperature, stirred for 2 h and quenched with aqueous NaHCC>3. The volatiles were
removed under reduced pressure. The residue was diluted with water and extracted with
5 CH2CI2. The organic layers were combined, dried (MgSCU) and the volatiles removed in
vacuo. Purification of the yellow oil by silica gel chromatography using 60% CH2CI2 in
ethyl acetate as the eluent and concentration in vacuo of the product rich fractions gave 4-
(4-^-butyl-2-nitrophenyl)pyrazole as a yellow crystalline solid (71 mg, 58%).
10 A mixture of 4-(4-/-butyl-2-nitrophenyl)pyrazole (0.27 mmol), 10 % Pd/C (0.2 eq by
weight of nitro compound) and NH4CO2H (2.7 mmol) in ethanol (3 mL) was stirred for
30 min and filtered through a bed of diatomaceous earth. The filtrate was concentrated
under reduced pressure and the residue dissolved in water. The solid was filtered, washed
with water and dried to give the product (54 mg, 93%).
15
Example 4 (Method I): Synthesis of 5-tert-butyl-2-(morpholin-4-yl)aniIine
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To a mixture of 2-nitro-4-tert-butyl phenol (5.4 g, 0.027 mol) and Et 3 N (5.85 mL, 0.042
mol) in methylene chloride (100 mL) at 0°C, triflic anhydride (5.2 mL, 0.030 mol) was
added via addition funnel. The reaction was stirred at room temperature for 2 days,
diluted with water (10 mL) and extracted with ethyl acetate (3X10 mL). The combined
organic extracts were washed with brine and dried (MgSC>4). Removal of the volatiles in
vacuo afforded 8.8 g (97% yield) of trifluoromethanesulfonic acid 4-tert-butyl-2-nitro-
phenyl ester, which crystallized in air.
A mixture of (400 mg, 1 .2 mmol) of the above triflate and morpholine (3 14 mL, 3.6
mmol) in acetonitrile (10 mL) was stirred at 80°C for 4 h. Removal of the of volatiles in
vacuo afforded 315 mg, 97 % yield of 4-(4-tert-butyl-2-nitrophenyl)morpholine, as a
yellow solid.
A mixture of the above nitro compound (320 mg, 1.2 mmol), ammonium formate (460
mg, 7.3 mmol) and 10% Pd/C (5 mg) in ethanol (20 mL) was stirred at 100°C for 1 h,
cooled to room temperature and filtered. Removal of the volatiles in vacuo provided 260
mg (93%) of the title compound.
Example 5: (Method J): Synthesis of 3-bromo-5-tert-butyl-2-[2-(morpholin-4-
yl)ethylamino] aniline
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A mixture of trifluoromethanesulfonic acid 4-tert-butyl-2-nitro-phenyl ester (400 mg 5 1.2
mmol) and N-(2-aminoethyl)morpholine (481 pL, 3.7 mmol) in acetonitrile (10 mL) was
stirred at 80°C for 4 h and cooled to room temperature. Removal of the volatiles in vacuo
provided a residue that was purified by flash chromatography using 15% ethyl acetate in
petroleum ether as eluent. Concentration in vacuo of the product-rich fractions provided
340 mg, 90% yield of the desired product, 4-^r/-butyl-2-nitro-N-[2-(morpholin-4-
yl)ethyl]aniline
To a solution of 4-tert-butyl-2-nitro-N-[2-(morpholin-4-yl)ethyl] aniline (240 mg, 0.8
mmol) in chloroform (1 mL) was added bromine (42 jjJL, 0.8 mmol) and an iodine
crystal. The mixture was stirred at room temperature for 1 h, diluted with water (10 mL)
and extracted with ethyl acetate (3X10 mL). The combined organic extracts were washed
with brine and dried (MgS04). Removal of the volatiles in vacuo afforded 300 mg, 99%
yield of the desired aryl bromide, 6-bromo-4-^r^-butyl-2-nitro-N-[2-(morpholin-4-
yl)ethyl]aniline
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To a solution of 6-bromo-4-tert-bu1yl-2-nitro-N-[2-(inorpholin-4-yl)ethyl]aniline (300
mg, 0.7 mmol) in 6 N HCl (15 mL) at 0°C was added stannous chloride (990 mg, 4.4
mmol), as a solution in 6N HCl (5 mL). The reaction was stirred for 1 h, basified with
20% potassium hydroxide and extracted with ethyl acetate (3X10 mL). The combined
organic extracts were washed with brine and dried (MgSC>4). Removal of the volatiles in
vacuo provided 200 mg, 72% yield, of the desired amine.
Examples 6-9 (Methods K-N) are representative procedures for the preparation of
intermediates of formula IV which may be used in Methods B-D (Scheme I). The
preparation of intermediates of formula IV may also be made with known starting
materials and by methods known to those skilled in the art including those to be found in
US serial number 09/484,638 incorporated herein by reference.
Example 6 (Method K): Synthesis of l-amino-4-(2-morpholin-4-yl-
ethoxy)naphthalene
To a mixture of 4-amino-l-naphthol hydrochloride (172.1 g) in 750 mL anhydrous THF
at -78 ° C was added dropwise over 60 min n-butyl lithium (490 mL of a 1 .60 M solution
in hexanes). After the addition was complete the mixture was allowed to warm to room
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temperature and then cooled to -78 C and di-ter/-butyl dicarbonate [(t-Boc)20 5 192 g]
in 200 mL THF was added over 20 min. The mixture was slowly warmed to room
temperature and stirred for 3 h and most of the volatiles removed in vacuo. The residue
was diluted with ethyl acetate (1 L) and washed with water (2 X 200 mL) and brine (200
mL) and filtered through diatomaceous earth and dried (MgSO^. Removal of the
volatiles in vacuo provided the N-f-Boc protected derivative (226 .1 g).
A mixture of the above N-^-Boc derivative (0.464 g) 5 4-(2-chloroethyl)morpholine
hydrochloride (0.3435 g) and powdered potassium carbonate (0.93 g) was heated in
acetonitrile (15 mL) at 80° C for 3 h, cooled to room temperature and diluted with ethyl
acetate and water. The organic layer was washed with water, brine, dried (MgSC>4) and
the volatiles removed in vacuo. Purification of the residue by flash chromatography using
12% hexanes in ethyl acetate as the eluent and concentration in vacuo of the product-rich
fractions afforded N-/-Boc-4-[2-(morpholin-4-yl)ethoxy]napth-l-yl-amine. A solution of
this intermediate (0.51 1 g) and HC1 (1 mL of 4M HC1 in dioxane solution) in 5 mL
dioxane was stirred at room temperature for 20 h. Removal of the volatiles in vacuo
provided 4-[2-(morpholin-4-yl)ethoxy]napth- 1 -yl-amine.
Example 7 (Method L): Synthesis of l-amino-4-(4-pyridinyl)oxynaphthalene.
To a stirred mixture of 4-amino-l-naphthol hydrochloride (2.5 g, 12.8 mmol) and 4-
chloropyridine hydrochloride (3.84 g, 29.2 mmol) in NMP (20 ml) was added potassium
terf-butoxide (6.0 g, 53.47 mmol) slowly. The mixture was heated at 120 °C for 6 h,
cooled to room temperature and diluted with water and dichloromethane. The combined
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organic extracts were washed with HC1 (2N), saturated aqueous NaHCCh and brine and
dried (Na2S04). Removal of the volatiles in vacuo afforded the product (0.5 g, 16 %).
Example 8 (Method M): Synthesis of l-amino-4-(3-(tetrahydropyran-2-yl-
oxy)propyn-l-yl)naphtha!ene.
To a solution of tetrahydro-2-(2-propynyloxy)-2//-pyran in anhydrous THF at -78° C
under inert atmosphere n-butyllithium (1.1 molar equivalents) was added via syringe.
After 1 h stirring at -78° C, tributyltin chloride (1 molar equivalent) was added and the
cooling bath was removed. After stirring at ambient temperature for 1 h the reaction
mixture was quenched with saturated NH4CI solution and extracted with ethyl ether. The
combined ethereal extracts were washed with brine and dried (MgSC>4). After filtration
all volatiles were removed in vacuo to produce the alkynyl tri-n-butylstannane as a
yellow oil which was used without further purification.
A mixture of N-^-Boc-4-bromonaphthylamine and the above alkynyl stannane (1.5 molar
equivalents) and BHT (20% weight equivalent) in toluene were heated at reflux under
inert atmosphere and treated with palladium (0) tetrakis-(triphenylphosphine) (0.1 molar
equivalent) When the reaction was complete, as judged by the color change to black, it
was cooled to room temperature. An aqueous solution of KF (5M) was added and the
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mixture was stirred vigorously for 6 h and extracted with ethyl acetate. The combined
organic extracts were washed with brine and dried (MgSC>4) ? filtered and all volatiles
were removed in vacuo. Purification of the residue by column chromatography afforded
the N-^-Boc intermediate. Removal of the N-/-Boc protecting group with HCI in dioxane
provided the amino intermediate.
Example 9 (Method N): Synthesis of l-amino-4-[2-(2-phenoxymethyImorpholin-4-
yl)-ethoxy] naphthalene dihydrochloride:
A solution of 2-phenoxymorpholine hydrochloride (0.098 g), N^N-di-zso-
propylethylamine (DIPEA) (149 uL), sodium iodide (0.32 g) and l-N-Boc-4-(2-
iodoethoxy)naphthylamine (0.176 g) in anhydrous DMF (1.5 mL) was heated at 40° C
overnight, cooled to room temperature and diluted with ethyl acetate and water. The
organic layer was washed with water and brine and dried (MgSC>4). Removal of the
volatiles in vacuo provided a residue that was purified by silica gel chromatography using
33% hexanes in ethyl acetate as the eluent. Concentration of the product rich fractions in
vacuo furnished 1 -N-Boc-4-[2-(2-phenoxymethylmorpholin-4-yl)-ethoxy]naphthylamine.
To a solution of the above t-Boc protected naphthylamine (0.18 g) in dioxane (1 mL)
was added HCI (0.47 mL of a 4N HCI in dioxane solution) and the mixture stirred
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overnight at room temperature, diluted with ether and cooled. The solid was filtered and
washed with ether and dried to provide l-amino-4-[2-(2-phenoxymethylmorpholin-4-yl)-
ethoxy ] naphthalene dihy drochloride .
5
Urea bond formation by Methods A-D is generally known in the art. A representative
example is given below.
10 Example 10 (Method B): l-[5-tert-butyl-2-methylphenyl]-3-[4-(2-morpholin-4-yl-
ethoxy)-naphthalen-l-yI]-urea
15
4-[2-(Morpholin-4-yl)ethoxy]napth-l-yl-amine (280 mg, 1.0 mmol) was dissolved in
dichloromethane (15 mL). An equal volume of sat. aqueous sodium bicarbonate was
added, and the biphasic solution was cooled to 0 °C. During the addition of phosgene
20 (1.93 M in toluene, 1.0 mL), stirring was stopped. Immediately afterward, stirring was
resumed for 15 min with the reaction mixture at 0 °C. The layers were separated, the
organics were dried over solid magnesium sulfate and concentrated to approximately 5
mL of solution. 5-/er/-Butyl-2-methylaniline (150 mg, 0.9 mmol) in dichloromethane (5
mL) was added, and the reaction mixture was stirred for 17 h at ambient temperature.
25 The desired compound was obtained after treatment of the reaction mixture with
petroleum ether and filtering to collect the precipitate (180 mg, 42%).
30
From the synthetic schemes and the example described above, the following
representative compounds of the formula(I) can be made:
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TABLE I
Structure
Chemical Name
F
F JJF
F-V^F
l-(2-Methoxy-5-pentafluoroethyl-phenyl)-3-{4-[2-(tetrahydro-pyran-4-
yl)-ethoxy]-naphthalen- 1 -yl} -urea
t v r iii
JO H H
l-(2-Methoxy-5-trifluoromethyl-pyridin-3-yl)-3-{4-[(pyridin-4-
ylmethyl)-amino]-naphthalen- 1 -yl} -urea
l-(2-Methoxy-54rimethylsilanyl-phenyl)-3-[4-(pyridin-4-ylmethoxy)-
naphthalen- 1 -y 11 -urea
1 1 II 1
H H \^
l-(3-tert-Butyl-phenyl)-3-[4-(3-pyridin-3-yl-propoxy)-naphthalen-l-
yll-urea
WWs ^
H H L^J
l-(4-Methoxy-biphenyl-3-yl)-3-{4-[2-(tetrahydro-pyran-4-yl)-ethoxy]-
naphthalen- 1 -yl} -urea
XT J J
H H l^j^J
l_(4-tert-Butyl-biphenyl-2-yl)-3-[4-(pyridin-4-ylmethoxy)-naphthalen-
l-yl]-urea
H H 1L ^
H
1 -(5 -tert-Buty 1-2-hydroxy-pheny l)-3 - [4-(2-thiomorpholin-4-yl-ethoxy)-
naphthalen- 1 -y 1] -urea
J H H llj^
K,C H,C —
l-(5-tert-Butyl-2-methoxy-3-propyl-phenyl)-3-[4-(3-morpholin-4-yl-
propyl)-naphthalen- 1 -yll-urea
CI X X^CCCi
H H il
HjC
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(l-methyl-2-morpholin-4-yl-
ethoxy)-naphthalen- 1 -yl]-urea
JO H H ll ^
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-morpholin-4-yl-2-oxo-
ethoxy)-naphthalen- 1 -yl]-urea
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-morpholin-4-yl-ethoxy)-
naphthalen- 1 -yl]-urea
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1- ^o-xen-i3Uiyi-z-ineinyi-Denzooxazoj- / -yi jo - |H--[o-^ieixanyciro-pyran-
2- yloxy)-prop- 1 -ynyl]-naphthalen- 1 -yl} -urea
H.C / CH.
i-jp-terc-DUtyi-z-rneinyi-pnenyi )-~>- \4-[z-(^,4-aiinetnoxy-pnenyi )-
ethoxy]-naphthalen- 1 -yl} -urea
l-(p-ten-outyi-z-morpnoiin-4-yi-pn^
ethoxy)-naphthalen- 1 -yl]-urea
H.C / CH.
VsVX °
H H
I-(^-tert-r>utyl-z-pyrroliain- l-yl-pnenyl j-J-[4-(z-morpnolin-4-yl-
propoxy)-naphthalen- 1 -yl] -urea
l -(!)-tert-r>utyl-z-pyrroliuin- 1 -yl-pnenyl j- J - (4-Lz-^z-metnoxymetnyi-
morpholin-4-yl)-ethoxy]-naphthalen-l-yl}-urea
H,C. PfiH.
1 J-lCl L JI> Lily L J dllU LllU-rYj/ ^JLlK^Lly L ) O ^jL y^^KJ KSll ll\^lliy I
morpholin-4-yl)-ethoxy]-naphthalen- 1 -yl} -urea
CH,
i j-ien-i5uiyi- i f -uiiTieinyidiTiino-Dipnenyi-j-yi ^-j)-[H--^j)-pipcricLin- 1 -
yl-prop- 1 -ynyl)-naphthalen- 1 -yl]-urea
p CHj
H3C
1 -(6- Methoxy-3 ,3 -dimethyl-inaan-5 -yl)- J - L4-(z-morpnolin-4-yl-
ethoxy)-naphthalen- 1 -yl]-urea
CH, H H \^
i-^o-ten-J3Utyi-z-cnioro-3-rnetnyi-pyriQin-4-yi j-j- \4-[z-^xeiranyaro-
pyran-4-yl)-ethoxy] -naphthalen- 1 -y 1 } -urea
H T i i T ]
\ — O H H 'v.^
i -^o-teri-x5Uiyi-Deiizo[ i , d juioxoi-^f-yi )-j>-\j-t-\ i -ineinyi-z-iTioipnoiiii-H-
yl-ethoxy)-naphthalen- 1 -yl]-urea
^.O H H lL
1 _^'7_Ayfp k i"Vl^Y n \/'_ 1 A Zl_tt*i TT1 ^tVl\/1 _ 1 *y A \&tv*A\\\Ff\TC\-C\~l\\v\C\\\Y\-£\-\T\\-'\ - f A -
i y 1 lViciiiUAy- 1 ? t T 5 t T-uiiiiCLiiy i i j 5 *t— icii<iiiy u.ivj i^uiiii^iiii-u-y i / ~j \ '
[2-( 1 -oxo-tetrahydro- 1 14-thiophen-3-yl)-ethoxy]-naphthalen- 1 -yl} -urea
CH, H H ll^J
l-(7-tert-Butyl-2 ? 4-dimethyl-benzooxazol-5-yl)-3-{4-[3-(tetrahydro-
pyran-3-yloxy)-prop- 1 -ynyl] -naphthalen- 1 -yl} -urea
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Q
> H H
i - [z-ivic iriuxy- j i -mc my l-cy cionexy i ^-pnciiy i j - j - \*t l ~ v+~ oao-
piperidin- 1 -yl)-prop- 1 -ynyl] -naphthalen- 1 -yl} -urea
H H ll^J
1 _ f7 -]VT<^tVirw \/_ ^ _ f 1 _m F»tVi \/1 _ r*\/r* 1 <~\T"\T~r^r>\/1 ^—t^Vi f^nx/ll-^ - f/1 ^ 9-mnmlirtl m-4-
i i z,"1vicliiu Ay j i —mc uiy j. ^y cnjpi upy i ^ puciiy i j j [_*t-^x,-iihji pinjiiii-T--
yl-ethoxy)-naphthalen- 1 -yl]-urea
J) H H IL J
H,C
i -LZ-ivicuiUAy- j>-^ i-piiciiy i-cyciupiupyi j-piicny ij-o-|^-^z,-iiiuipiiuiiii- < +-
yl-propoxy)-naphthalen- 1 -yl]-urea
c
O
c
M/X O
3 H H \^
i-[z-ivieinoxyo-^z-meinyi-re j-pnenyij-j-LH— ^z-
thiomorpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-urea
F
H H ^LijJ
i -[z-ivicinoxy- j-^ j-TTiiiuororncinyi-Dicycio[ i . i . i jpeiu- 1 -yi ^-pnenyij- j-
[4-(2-pyridin-4-yl-ethoxy)-naphthalen- 1 -yl]-urea
l - Lj-J3ruiiiu- j-icr i-uuLyi-z-^z-iiiurpiiuiiii-H-y i-cuiy iciiiiiiiu ^-piicny ij- d~
[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-urea
i -[ j-lci L-J3Uiyi" \ i -iiicLiiyi- 1 xi-iiiinj.d.z,L)i-*T-y i j-puciiy ij-j)-|_*t-^z,-
morpholin-4-yl-2-oxo-ethoxy)-naphthalen- 1 -yl]-urea
o
1 -r3-tert-Butvl-5-f2-Dvrrolidin- 1 -vl-ethvlVDhenvn-3-r4-fDvridin-4-
ylmethoxy)-naphthalen- 1 -yl]-urea
1 -r3-tert-Butvl-5-r3-Dvrrolidiii-l -vl-DroD-1 -vnvlVDhenvll-3-r4-f2-
pyridin-4-yl-ethyl)-naphthalen- 1 -yl]-urea
CHj H H ll^-J
1 ~[^-C7-\m\c\ii7cA~ 1 -vl-ptHoxv^-na'nVitlifllp'n-1 -v11-^-^4-rnptliv1-Hi , n}iPTiv1-
i i ^ i l niiiutiijUi i y i v inv/A y i iiciLyi in iciiwii. x y j.j — ' \ • iiivm v i uiijli\sii y i
3-yl)-urea
1 _ 9-Tm i H - 1 -vl -ptHov v^-n ar>VitVia Ipn - 1 -vIl-^-r^-mptVinw-S-M -
i i ^ i A niiiUtttiVJi i y i v iiiuA y i iiciL^ixtiiciiwix j. y ij ^ i z< iiiw liiw^v y «^ \ i
methyl- 1 -phenyl-ethyl)-phenyl]-urea
X> H H
l-[5-(l-Cyano-cyclopropyl)-2-methoxy-phenyl]-3-[4-(2-moipholin-4-
yl-propoxy)-naphthalen- 1 -y l]-urea
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JO H H V ^
l i -riyaroxymetnyi-cyciopropyi j-z-metnoxy-pnenyij- d- |4-
[(pyridin-4-ylmethyl)-amino]-naphthalen- 1 -yl} -urea
i -[3-ien-r>uiyi- 1 -^z-QieinyiaixLino-eiiiyi j-z-oxo- 1 ,z-QinyQro-pyriain-j-
yl]-3- {4-[3-(2-methoxymethyl-morpholin-4-yl)-prop- 1 -ynyl]-
naphthalen- 1 -y 1 } -urea
1 -(5-tert-Butyl--2-phenoxy-pneny
4-yl)-ethoxy]-naphthalen- 1 -yl} -urea
H
l-L5-tert-Bu1yl-z-(lH-pyrazol-4-ylj-^^
ethoxy)-naphthalen- 1 -yl]-urea
H.C / CM.
.N. H H K^J
1 -L3-tert-rJutyl-z-(z, j-aioxo-pyrroiiclin- 1 -yl j-pnenylj- d- {4-[z-
(tetrahydro-pyran-4-yl)-ethoxy]-naphthalen- 1 -y 1 } -urea
1 -L5-tert-Butyl-z-(z-metnyl-pynm {4-[z-( 1 -oxo-
tetrahydro- 1 14-thiophen-3-yl)-ethoxy]-naphthalen- 1 -yl} -urea
1 - f S-tprt-Ri i ta/1 -9 -tnpfliox v-T^vri rl in-^-vl^-^ - iA.-\ r )-( 1 -ox o-
i i j ici i jjui y i l iii^tiiuA y u y i iuiii j y 1 1 j it \~ \ wau
thiomorpholin-4-yl)-ethoxy]-naphthalen- 1 -yl]-urea
H H V ^
l - [ j -tert-outy i-z-^z-morpnoiin-4-y i-z-oxo-etnoxy j-pneny i j - 5 - (4- [o-^z-
pyridin-4-yl-ethy l)-pyridazin-3 -yl]-naphthalen- 1 -yl } -urea
M, 'x
• o
l-[5-tert-Butyl-2-(2-moj^holm-4-yl-2-oxo-ethylamino)-^
[3-(tetrahydro-pyran-3-yloxy)-prop- 1 -ynyl] -naphthalen- 1 -yl} -urea
1 -[ j-tert-outyl-z-(o-iTietiiyl-pynain- J-ylj-pxienyij-3-[4-(Z-pyriain-z-yi-
ethoxy)-naphthalen- 1 -yl]-urea
i -|_ j-icrL-jjuiyi-z-iiicLiioxy- j-^j-iiiurpiiuiiii-^-y i-j)-uxu-piupciiy i j
phenyl]-3- {4-[2-(2,6-dimethyl-morpholin-4-yl)-ethoxy]-naphthalen- 1 -
yl}-urea
l-[5-tert-Butyl-3-(2-diethylamino-ethoxy)-2-methoxy-phenyl]-3-[4-(2-
thiomorpholin-4-yl-ethoxy)-naphthalen- 1 -yl] -urea
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i -[ j-ieri-ijULyi- j-^z-pyrroiiGin- i -yi-exnyi j-ucnzoiurd,ii- / -y i j-j)-^-
(pyridin-4-ylmethoxy)-naphthalen- 1 -y l]-urea
1 -r^.tprt-Riitv1-4-0-HirnptViv1^rninn-pth vl^-l-nxn-^ 4-rlihvr1m-?H-
benzo[ 1 ,4]oxazin-8-yl]-3-[4-(3-piperidin- 1 -yl-prop- 1 -ynyl)-
naphthalen- 1 -yl]-urea
i - z-i z,u-i-jiiiiciiiy i~iiiLiipiiuiiii _i T-y i y-cunjAy j~iidpiiiiidicii~ i yi/ j [J
(1,1 -dimethyl-propyl)-2-methoxy-pheny 1] -urea
CH, H H il ^0
* H,C
I- |^-[z-^o ? H-iJirncinoxy-pnenyi j-einoxyj-napninaien- i-yij o-^ j>-
methyl-naphthalen-2-yl)-urea
\kxxx y
• 1 1 9
WjC CH,
1 - {4-[3-(2-Methoxymethyl-morpholin-4-yl)-prop- 1 -ynyl]-naphthalen-
1 -yl} -3-(3-methoxy-naphthalen-2-yl)-urea
^^^^^^^
i - 1 o - ten- r> ury i- z -rneinoxy- d - [ z - ^ i -rnetny i -p lperiain-^f-yio xy ) - ciny i j -
phenyl}-3-[4-(3-pyridin-3-yl-propoxy)-naphthalen-l-yl]-urea
9_r4-tprt-Riitvl-?-^- 1 -oxo-tetrahvdro-thionhen-l-vlVethoxvl-
naphthalen- 1 -yl} -ureido)-phenoxy]-N-methyl-acetamide
H£T CH,
j -iGii-J3Uiyi-3- 1 j-L*+-^j-piperiain- i-yi-prop- 1 -ynyi ^-napninaien- 1 -
y^-ureidoJ-phenyO-NjN-dimethyl-propionamide
CH,
H H
d - ( j - ten- Jt>u ty i-z -me inoxy- d - \ j - [ft- -py riain- z -y i -einoxy j -napn inaien-
1 -yl]-ureido} -phenyl)-acrylamide
H
'f-tert-rJuiyi-z- \ j-[^-^j-moi^noiin- £ f-yi-prop- i-ynyi j-napninaieii- 1 -yij-
ureido } -benzamide
0
±>i-^j-icri-jjULyi- j- ^ j-|_ t T-i v z-iiiuipmJini -A t-y i-^JiopuAy ^-iidpiiiiiciicii- 1 y i j
ureido}-phenyl)-2-morpholin-4-yl-acetamide
N-(4-tert-Butyl-2- {3-[4-(3-morpholin-4-yl-propyl)-naphthalen- 1 -yl]-
ureido}-phenyl)-2-morpholin-4-yl-acetamide
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^f* ^~xj
Qii^A^ H H \jfS>
iN-L^-icri-ouiy i-z-^j>- \H— [ j-^ieiranyaro-pyran-z-yioxy j-prop- 1 -ynyij-
naphthalen- 1 -y 1 } -ureido)-phenyl] -acetamide
H,cX,CH,
H H ^L-4?J
i-^j-ien-jjuiyi-z-rncinoxypnenyi j-j-[4-^z-arninopyriQin-4-yi-oxy j-
naphthalen- 1 -y l]-urea,
T ^
X ^v. ^0 ^-^ ,NH
1 j-tert-outyi-z-metnoxypnenyi j-3-[4-^z-^metiiyiamino jpyriain-4-yi-
oxy)-naphthalen- 1 -yl]-urea,
^J-^ N N T| ^1
-O H M ^L-jsJ
i-^D-ten-rsuiyi-z-nietnoxypiienyi j-j-L*r- ^z-^pnenyiamino jpynam-4-yi-
oxy )-naphthalen- 1 -yl] -urea,
T ¥ V T ]
.,0 H H
H,C
i -( j-terx-rJULyi-z-nietnoxypnenyi j- j-[h-^z-^ i -
phenylethylamino)pyridin-4-yl-oxy)-naphthalen- 1 -yl]-urea
M,C,
c
,6 H H
i j-ieri-outyi-z-rneinoxypiienyi j- D-\y\-\£-\ i -
phenylethylamino)pyrimid-4-yl-methyl)-naphthalen- 1 -yl]-urea
r Ol
X - _ ,HH
H H ll^J
1 -( S-tpr+-Rntv1-?-mpthoxvnhpnv1 \~'\~\A-( r ) -( 1 -
i i j iti i jj uiy i l iiitiiiUA y until y 1 1 j I t \~ \
phenylethy lamino)pyridin-4-y 1-methy l)-naphthalen- 1 -y 1] -urea
r Q
LI A 11
H H
l-C5-tert-Butvl-2-methoxvDhenvn-3-r4-f2-n-
phenylethylamino)pyridin-4-yl-thio)-naphthalen- 1 -yl]-urea
c
„CH 3
VsiXo
Hj H H
1 -r5-tert-hutvl-2-methvl'Dhenvll-3-r4-r 4-nvridinvloxvVnaDhthalen- 1 -
X 1 «y L-^^X L* Km- %> j X 111V 111 y X yj 11V11 V X 1 1 ■ I T T X lulll T l\//\ Jf # L/ll tlltilvli X
yl]-urea
CH, H H
1 -r5-tert-butvl-2-methvlDhenvll-3-r4-r3-DvridinvloxvVnaDhthalen- 1 -
X 1 l^^rf'X b *_T X XX I'll T X m-r 11V11 T 1 1 [ \ _J HIT 1X^' »- T / 11 V* L^ll V-tlU-L * A
yl]-urea
O H H l^fJ k^>^/ J
l-[5-tert-butyl-2-methoxyphenyl]-3-[4-(2-(2-
phenoxymethyl)morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-urea
CH, H H
l-[5-tert-butyl-2-methylphenyl]-3-[4-(2-morpholin-4-yl-ethoxy)-
naphthalen- 1 -yl]-urea
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l-[3-acetamido-5-trifliioromethyl-2-methylthiophenyl]-3-[4-(3-
pyridinyloxy)-naphthalen- 1 -yl]-urea
1-(54ert-Butyl-2-methoxyphenyl)-3-[4-(2-methoxy-pyridin-4-yl-oxy)-
naphthalen-1-yl]-urea
1-(5-tert-Butyl-2-methoxyphenyl)-3-[4-(3,4-dimethoxyphenyl-oxy)-naphthalen-
1-yl]-urea
1-(54ert-Butyl-2-methoxyphenyl)-3-[4-(4-methylsulfonyl-oxy)-naphthalen-1-yl]-
urea
1-(5-tert-Butyl-2-methoxyphenyl)-3-[4-(2-methyl-pyridin-4-yl-oxy)-naphthalen-
1-(5-tert-Butyl-2-methoxyphenyl)-3-[4-(1H-pyrolo[2,3-b]pyridin-4-yl-oxy)-
naphthalen-1 -yl]-urea
1-(5-tert-Butyl-2-methoxyphenyl)-3-[4-(1H-pyrazolo[2,3-b]pyridin-4-yl-oxy)-
naphthalen-1-yl]-urea
1-(5-tert-Butyl-2 f 3-dimethoxyphenyl)-3-[4-(2-methoxy-pyridin-4-yl-oxy)-
naphthalen-1-yl]-urea
5-tert-Butyl-2-methoxy-3-{3-[-(pyridin-4-yl-oxy)naphthalen-1-
yl]ureido}benzamide
Morpholine-4-carboxylic acid (5-tert-butyl-2-methoxy-3-{3-[-(pyridin-4-yl-
oxy)naphthalen-1-yl]ureido}phenyl)amide
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N-(5-tert-Butyl-2-methoxy-3-{3-[-(pyridin-4-yl-oxy)naphthalen-1-
yl]ureido}phenyl)acetamide
3-(5-tert-Butyl-2-methoxy-3-{3-[-(pyridin-4-yl-oxy)naphthalen-1-
yi]ureido}phenyl)-1 ,1-dimethylurea
1-(1-Benzyl-1,2,3,4-tetrahydro-quinolin-4-y^^
urea
1-(54ert-Butyl-2nTiethyl-phenyl)-3^^
quinolin-4-yl]-urea
1 -(5-tert-Butyl-2-methyl-phenyl)-3-[1 -(3,5-dimethoxy-benzyl)-1 ,2,3,4-
tetra hyd ro-qu inol i n-4-yJ]-u rea
1-(5-tert-Butyl-2-methyl-phenyl)-3-(1-pyridin-4-yimethyl-1 ,2,3,4-tetrahydro-
quinolin-4-yl)-urea
1 -(5-tert-Butyl-2-methyl-phenyl)-3-[1 -(pyridine-4-carbonyl)-1 ,2, 3,4-tetrahydro-
quinolin-4-ylj-urea
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[1-(pyridine-4-carbonyl)-1 ,2,3,4-
tetra hy d ro-q u i nol i n-4-y I]- u rea
1 -(5-tert-Butyl-2-methoxy-phenyl)-3-[1 -(4-methoxy-benzoyl)-1 ,2,3,4-
tetrahydro-quinolin-4-yl]-urea
1-(54ert-Butyl-2-methoxy-phenyl)-3-[1-(3,4-dimethoxy-benzoyl)-1 ,2,3,4-
tetrahydro-quinolin-4-yl]-urea
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1-[4-(2-Amino-pyridin-4-yloxy)-naphthalen-1-yl]-3-(5-tert-butyl-2,3-dim
phenyl)-urea
1-(5-tert-Butyl-2,3-dimethoxy-phenyl)-3-[4-(2-methylamino-pyridin-4-yloxy)-
naphthalen-1 -yl]-urea
1-(5-tert-Butyl-2,3-dimethoxy-phenyl)-3-{4-[2-(1-phenyl-ethylamino)-pyridin-^^
yloxy]-naphthalen-1 -yl}-urea
nil
B H
NHj
1-[4-(2-Amino-pyridin-4-yloxy)-naphthalen-1-yl]-3-(5-tert-butyl-2-methoxy-
pyridin-3-yl)-urea
N.
1-(5-tert-Butyl-2-methoxy-pyridin-3-yl)-3-[4-(2-methylamino-pyridin-4-yloxy)-
naphthalen-1 -yl]-urea
1-(5-tert-Butyl-2-methoxy-pyridin-3-yl)-3-{4-[2-(1-phenyi-ethylamino)-pyridin-4-
yloxy]-naphthalen-1 -yl}-urea
1 -(5-tert-Butyl-2-methylphenyl)-3-[1 -(2-pyridin-4-yl-acetyl)-1 ,2,3,4-
tetrahydroquinolin-4-yl]-urea
1 -(5-tert-Butyl-2-methoxyphenyl)-3-[1 -(2-pyridin-4-yl-acetyl)-1 ,2,3,4-
tet ra hyd roq u i nol i n-4-y l]-u rea
and the pharmaceutically acceptable salts thereof.
Preferred compounds are selected from:
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1-(5-tert-Butyl-2-methoxyphenyl)-3-[4-(2-methoxy-pyridin-4-yl-oxy)-
naphthalen-1 -yl]-urea
1-(5-tert-Butyl-2-methoxyphenyl)-3-[4-(2-methyl-pyridin-4-yl-oxy)-naphthalen-
1-yl]-urea
1-(5-tert-Butyl-2,3-dimethoxyphenyl)-3-[4-(2-methoxy-pyridin-4-yl-oxy)-
naphthalen-1-yl]-urea
5-tert-Butyl-2-methoxy-3-{3-[-(pyridin-4-yl-oxy)naphthalen-1-
yl]ureido}benzamide
Morpholine-4-carboxylic acid (5-tert-butyl-2-methoxy-3-{3-[-(pyridin-4-yl-
oxy)naphthalen-1-yl]ureido}phenyl)amide
N-(5-tert-Butyl-2-methoxy-3-{3-[-(pyridin-4-yl-oxy)naphthalen-1-
yl]ureido}phenyl)acetamide
3-(5-tert-Butyl-2-methoxy-3-{3-[-(pyridin-4-yl-oxy)naphthalen-1-
yl]ureido}phenyl)-1 t 1-dimethylurea
1-[4-(2-Amino-pyridin-4-yloxy)-naphthale^
phenyl)-urea
1-(5-tert-Butyl-2 ) 3-dimethoxy-phenyl)-3-[4-(2-rnethylamino-pyridin-4-ytoxy)-
naphthalen-1 -yl]-urea
1-(5-tert-Butyl-2,3-dimethoxy-phenyl)-3-{4-[2-(1-phenyl-ethylamino)-pyridin
4-yloxy]-naphthalen-1 -yl}-urea
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1-[4-(2-Amino-pyridin-4-yloxy)-naphthalen-1-yl]-3-(5-tert-butyl-2-methoxy-
pyridin-3-yl)-urea
1-(5-tert-Butyl-2-methoxy-pyridin-3-yl)-3-[4-(2-methylamino-pyridin-4-yloxy)-
naphthalen-1-yl]-urea
1-(5-tert-Butyl-2-methoxy-pyridin-3-yl)-3-{4-[2-(1-phenyl-ethylamino)-pyridin-
4-yloxy]-naphthaIen-1-yl}-urea
and the pharmaceutically acceptable salts thereof.
The following compounds found in Table I were evaluated, all had IC50 < 10 uM in the
"Inhibition of TNF Production in THP Cells" assay described below:
1 -(5-tert-Butyl-2-methylphenyl)-3-[4-(2-aminopyridin-4-yl-oxy)naphthalen- 1 -yl]urea;
l-(5-tert-Butyl-2-moipholin-4-yl-phe
l-[3-Bromo-5-tert-butyl-2-(2-morpholin-4-yl-ethylamino)-phenyl]-3-[4-(2-morphoH
yl-ethoxy)-naphthalen- 1 -yl]-urea;
1 -[5-tert-butyl-2-methylphenyl]-3-[4-(4-pyridinyloxy)-naphthalen- 1 -yl]-urea;
l-[5-tert-butyl-2-methylphenyl]-3-[4-(3-pyridinyloxy)-naphthalen-l-yl]-urea;
l-[5-tert-butyl-2-methoxyphenyl]-3-[4-(2-(2-phenoxymethyl)morpholin-4-yl-ethoxy)-
naphthalen- 1 -yl]-urea and
1 -[5 -tert-butyl-2-methylphenyl]-3 - [4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-urea.
yl]-urea;
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ASSESSMENT OF BIOLOGICAL PROPERTIES
Inhibition of TNF Production in THP Cells
5 The inhibition of cytokine production can be observed by measuring inhibition of TNFa
in lipopolysaccharide stimulated THP cells (for example, see W. Prichett et aL, 1995, J.
Inflammation, 45, 97). All cells and reagents were diluted in RPMI 1640 with phenol red
and L-glutamine, supplemented with additional L-glutamine (total: 4 mM), penicillin and
streptomycin (50 units/ml each) and fetal bovine serum (FBS, 3%) (GIBCO, all cone.
10 final). Assay was performed under sterile conditions; only test compound preparation was
nonsterile. Initial stock solutions were made in DMSO followed by dilution into RPMI
1640 2-fold higher than the desired final assay concentration. Confluent THP.l cells
(2xl0 6 cells/mL, final cone; American Type Culture Company, Rockville, MD) were
added to 96 well polypropylene round bottomed culture plates (Costar 3790; sterile)
15 containing 125 jaL test compound (2 fold concentrated) or DMSO vehicle (controls,
blanks). DMSO concentration did not exceed 0.2% final. Cell mixture was allowed to
preincubate for 30 min, 37°C, 5% CO2 prior to stimulation with lipopolysaccharide (LPS;
1 )Lxg/mL final; Siga L-2630, from E.coli serotype 01 1 1.B4; stored as 1 mg/mL stock in
endotoxin screened distilled H2O at -80°C). Blanks (unstimulated) received H2O vehicle;
20 final incubation volume was 250 jlxI. Overnight incubation (18-24 hr) proceeded as
described above. Assay was terminated by centrifuging plates 5 min, room temperature,
1600 rpm (400 x g); supernatants were transferred to clean 96 well plates and stored -
80°C until analyzed for human TNFa by a commercially available ELISA kit (Biosource
#KHC3015, Camarillo, CA). Data was analyzed by non-linear regression (Hill equation)
25 to generate a dose response curve using SAS Software System (SAS institute, Inc., Cary,
NC). The calculated IC50 value is the concentration of the test compound that caused a
50% decrease in the maximal TNFa production.
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Inhibition of other cytokines
By similar methods using peripheral blood monocytic cells, appropriate stimuli, and
commercially available ELISA kits (or other method of detection such as
5 radioimmunoassay), for a particular cytokine, inhibition of IL-lp, GM-CSF, IL-6 and IL-
8 can be demonstrated (for example, see J.C. Lee et al. 9 1988, Int. J, ImmunopharmacoL ,
10, 835).
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What is claimed is:
1 . A Compound of the formula (I):
X
N N
I I
H H
(I)
wherein:
Gis:
an aromatic Ce-\o carbocycle or a nonaromatic C3_iocarbocycle saturated or unsaturated;
a 6-10 membered heteroaryl containing 1 or more heteroatoms chosen from 0,N and S;
or
a 5-8 membered monocyclic heterocycle or a 8-1 1 membered bicyclic heterocycle, each
containing one or more heteroatoms chosen from 0,N and S;
wherein G is substituted by one or more Ri, R2 or R3;
Ar is:
phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl,
dihydrobenzofuranyl, dihydrobenzothienyl, indolenyl, benzothiophenyl,
tetrahydroisoquinolinyl, benzimidazolyl, benzofuranyl, indanyl, indenyl or indolyl each
optionally substituted by one or more R4 or R 5 groups;
L is a:
Ci_io saturated or unsaturated branched or unbranched carbon chain;
wherein one or more methylene groups are optionally independently replaced by
heteroatoms chosen from O, N and S(0) m ; and
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wherein said L is optionally substituted with 0-2 oxo groups and one or more C1.4
branched or unbranched alkyl optionally substituted by one or more halogen atoms;
Qis:
phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, benzimidazolyl,
fiiranyl, thienyl, pyranyl, naphthyridinyl, pyrazinyl, pyrazolyl, triazolyl, tetrazolyU
pyrazolo[3,4-b]pyrimidinyl, purinyl, pyrrolo[2,3-b]pyridinyl, pyrazolo[3,4-b]pyridinyl,
tubercidinyl, oxazo[4,5-£]pyridinyl and imidazo[4,5-Z>]pyridinyl, which are optionally
substituted with one to three Ci_6 alkyl, Ci_6 alkoxy, hydroxy, amino, mono- or di-(Ci_3
alkyl)amino, mono- or di-(phenyl-Ci_3 alkyl)amino, C1-6 alkyl-S(0) m , phenyl- C1-3-
alkoxy or phenylamino wherein the phenyl ring is optionally substituted with one to two
halogen, Ci_6 alkyl or Ci_6 alkoxy;
tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxanyl,
morpholino, thiomorpholino, thiomorpholino sulfoxide, thiomorpholino sulfone,
piperazinyl, piperidinyl, piperidinonyl, tetrahydropyrimidonyl, cyclohexanone,
cyclohexanol, pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene
sulfone, tetramethylene sulfide, tetramethylene sulfoxide or tetramethylene sulfone which
are optionally substituted with one to three d-6 alkyl, C1-6 alkoxy, hydroxy, mono- or di-
(Ci_3 alky l)amino-C 1.3 alkyl, phenylamino-Ci-3 alkyl or C1-3 alkoxy-Ci_ 3 alkyl;
C1-6 alkoxy, secondary or tertiary amine wherein the amino nitrogen is covalently
bonded to C1.3 alkyl or Cm alkoxyalkyl, phenylamino, wherein the phenyl ring is
optionally substituted with one to two halogen, Ci_6 alkoxy, hydroxy or mono- or di-(Ci_3
alkyl)amino, Cue alkyl-S(0) m or phenyl-S(0) m wherein the phenyl ring is optionally
substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(Ci_3
alkyl) amino;
each Ri is independently:
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C3-10 branched or unbranched alkyl optionally partially or fully halogenated, and
optionally substituted with one to three C3.10 cycloalkyl, hydroxy, phenyl, naphthyl ,
pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl,
furyl, isoxazolyl or isothiazolyl; each of the aforementioned being optionally substituted
with 1 to 5 halogen, Ci_6 branched or unbranched alkyl which is optionally partially or
fully halogenated, C3.8 cycloalkyl, Cs-s cycloalkenyl, hydroxy, cyano, C1-3 alkoxy which
is optionally partially or fully halogenated and NH2C(0) or mono- or
di(C 1 _3)alkylaminocarbonyl;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl,
bicyclohexanyl or bicycloheptanyl, which are optionally partially or fully halogenated
and optionally substituted with one to three Ci_3 alkyl groups optionally partially or fully
halogenated, cyano, hydroxy Ci^alkyl or aryl; or an analog of cyclopropyl, cyclobutyl,
cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or
bicycloheptanyl wherein one to three ring methylene groups are replaced independently
by O, S(0) m , CHOH, >CO, >C=S or NH;
C3-10 branched or unbranched alkenyl optionally partially or fully halogenated, and
optionally substituted with one to three C1-5 branched or unbranched alkyl, phenyl,
naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl,
thienyl, furyl, isoxazolyl or isothiazolyl, each of the aforementioned are optionally
substituted with 1 to 5 halogen, Q.6 branched or unbranched alkyl optionally partially or
fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl,
bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, hydroxy, cyano, C1-3 alkoxy
optionally partially or fully halogenated, NH2C(0) or mono- or di(Ci_
3 )alkylaminocarbonyl; the C3.10 branched or unbranched alkenyl is optionally interrupted
by one or more O, N or S(0) m ;
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl,
bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C1-3
alkyl groups;
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cyano, halogen;
methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl;
silyl containing three C1.4 independently branched or unbranched alkyl groups optionally
5 partially or fully halogenated;
C2-6 branched or unbranched alkyl-C(O), C2-6 branched or unbranched-S, C2-6 branched
or unbranched-S(O), C2-6 branched or unbranched-S(0)2;
C2-6 alkynyl branched or unbranched carbon chain optionally partially or fully
10 halogenated, wherein one or more methylene groups are optionally replaced by O, NH
and S(0) m and wherein said alkynyl group is optionally independently substituted with 0-
2 oxo groups, pyrroldinyl, pyrrolyl, one or more Ci_4 branched or unbranched alkyl
optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl,
piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or C 1-4 branched or unbranched
15 alkylamino optionally substituted by one or more halogen atoms;
each R2, R4, and R5 is independently
a C1-6 branched or unbranched alkyl optionally partially or fully halogenated, acetyl,
20 aroyl, C1-4 branched or unbranched alkoxy optionally partially or fully halogenated,
halogen, methoxycarbonyl or phenylsulfonyl;
Ci_6 alkoxy, hydroxy, amino, or mono- or di-(Ci_4 alkyl)amino, cyano, halogen;
25 ORe;
nitro; or
mono- or di-(Ci_4 alkyl)amino-S(0)2 optionally partially or fully halogenated, or
H2NSO2;
30 each R3 is independently:
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hydrogen, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,
pyrrolidinyl, imidazolyl, pyrazolyl, thienyl, fiiryl, tetrahydrofuryl, isoxazolyl, thiazolyl,
oxazolyl, triazolyl, tetrazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl,
benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl,
benzothiofiiranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl,
quinazolinyl, purinyl or indazolyl wherein each of the aforementioned is optionally
substituted with one to five phenyl, naphthyl, heterocycle or heteroaryl wherein the
heterocyclic and heteraryl moiety is as hereinabove described in this paragraph , Ci_6
branched or unbranched alkyl which is optionally partially or fully halogenated,
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl,
bicyclohexanyl, bicycloheptanyl, phenyl Ci_s alkyl, naphthyl C1-5 alkyl, halogen, hydroxy,
oxo, cyano, C1-3 alkoxy optionally partially or fully halogenated, phenyloxy,
naphthyloxy, heteraryloxy wherein the heterocyclic moiety is as hereinabove described in
this paragraph, nitro, amino, mono- or di-(Ci_3)alkylamino, phenylamino, naphthylamino,
heterocyclic or heteroaryl amino wherein the heterocyclic or heteroaryl moiety is as
hereinabove described in this paragraph, NH2C(0), a mono- or di-(Ci_3)alkyl
aminocarbonyl, C1-5 alkyl-C(0)-Ci_4 alkyl, amino-Ci-5 alkyl, mono- or di-(Ci_
3)alkylamino-Ci-5 alkyl, amino-S(0)2, di-(Ci_3)alkylamino-S(0)2, R7-Ci_5 alkyl, Rg-Ci.5
alkoxy, R9-C(0)-Ci_5 alkyl, R10-C1-5 alkyl(Rn)N, carboxy-mono- or di-(Ci_ 5 )-alkyl-
amino;
a fused aryl selected from benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl,
tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heterocycle
selected from cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine,
cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine,
cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline,
cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline,
cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole,
cyclohexanobenzimidazole, cyclopentanobenzoxazole, cyclohexanobenzoxazole,
cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and
cyclohexanothiophene; wherein the fused aryl or fused heterocyclic ring is optionally
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independently substituted with 1 to 3 groups selected from phenyl, naphthyl, pyridinyl,
pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl,
isoxazolyl, isothiazolyl, Ci_6 branched or unbranched alkyl optionally partially or fully
halogenated, halo, cyano, C1-3 alkoxy optionally partially or fully halogenated,
phenyloxy, naphthyloxy, heterocyclicoxy heteroaryloxy wherein the heterocyclic or
heteroaryl moiety is as hereinabove described in this paragraph, nitro, amino, mono- or
di-(Ci-3)alkylamino, phenylamino, naphthylamino, heterocyclicamino or heteroarylamino
wherein the heterocyclic or heteroaryl moiety is as hereinabove described in this
paragraph, NH2C(0), a mono- or di-(Ci-3)alkyl aminocarbonyl, C1-4 alkyl-OC(O), C1.5
alkyl-C(0)-Ci_4 branched or unbranched alkyl, an amino-Ci.5 alkyl, mono- or di-(Ci_
3 )alkylamino-Ci_5 alkyl, Ri 2 -Ci_5 alkyl, R13-C1.5 alkoxy, Ri 4 -C(0)-Ci_ 5 alkyl and R15-C1.5
alkyl(R 16 )N;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl,
bicyclohexanyl or bicycloheptanyl optionally partially or fully halogenated and
optionally substituted with one to three Ci_ 3 alkyl groups, or an analog of cyclopropyl,
cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl
or bicycloheptanyl wherein one to three ring methylene groups are replaced
independently by O, S(0) m , CHOH, >C-0, >C=S or NH;
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl,
bicyclohexenyl or bicycloheptenyl each optionally substituted with one to three C1-3 alkyl
groups;
Ci_4 branched or unbranched alkyl-phenyl-C(0)-Co-4 branched or unbranched alkyl, C1-4
branched or unbranched alkyl-C(0)-Co-4 branched or unbranched alkyl, Cm branched or
unbranched alkyl-phenyl-S(0) m -Co-4 branched or unbranched alkyl;
C1-6 branched or unbranched alkyl or Cue branched or unbranched alkoxy each is
optionally partially or fully halogenated or optionally substituted with Ri 7 ;
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Co-6 branched or unbranched alkyl optionally substituted with ORi8;
amino or C1-C5 branched or unbranched mono- or di-alkylamino optionally substituted
with R19;
5 Cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or cycloheptyloxy which
are optionally partially or fully halogenated and optionally substituted with one to three
Ci_3 alkyl groups optionally partially or fully halogenated, wherein one to three ring
methylene groups are replaced independently by O, S(0) m , CHOH, >C=0, >C=S or NH;
10 R 20 C(O)N(R 2 iK R22O- or R 23 R 24 NC(0)-; R 26 (CH 2 ) m C(0)N(R 21 )- or
R 26 C(0)(CH 2 ) m N(R 21 )s
C 2 _6alkenyl substituted by R 2 3R 2 4NC(0)-;
1 5 C2-6 alkynyl branched or unbranched carbon chain optionally partially or fully
halogenated, wherein one or more methylene groups are optionally replaced by O, NH,
S(O), S(0) 2 or S and wherein said alkynyl group is optionally independently substituted
with 0-2 oxo groups, pyrroldinyl, pyrrolyl, one or more Q_4 branched or unbranched
alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino,
20 piped dine, piperazine, imidazole, phenyl, pyridine, tetrazole, or C 1.4 branched or
unbranched alkylamino optionally substituted by one or more halogen atoms; or
aroyl;
25 R<5 is a:
C1-4 branched or unbranched alkyl optionally partially or fully halogenated and optionally
substituted with R 2 6 ;
each R 7 , Rs, R9, Rio, Ri2, Ri3, R14, R15, Rn, Ri9> R 2 5 and R 26 is independently:
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nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl or
alkylamino mono- or di-Co-4 branched or unbranched optionally partially or fully
halogenated;
5 each Rj i and Ri6 is independently:
hydrogen or Cm branched or unbranched alkyl optionally partially or fully halogenated;
Ris is independently:
hydrogen or a C1-4 branched or unbranched alkyl optionally independently substituted
10 with oxo or R25;
R20 is:
Ci-10 branched or unbranched alkyl optionally partially or fully halogenated, phenyl or
pyridinyl;
15
R21 is:
hydrogen or C 1.3 branched or unbranched alkyl optionally partially or fully halogenated;
each R22 ? R23 and R24 is independently:
20 hydrogen, Cue branched or unbranched alkyl optionally substituted by carbonylamino-
mono- or di-Ci-3alkyl or amino-mono or diCi-3alkyl or wherein said C1-6 alkyl optionally
partially or fully halogenated and optionally interrupted by one or more O, N or S,
phenyl, pyridine, mono- or di-Co-4 branched or unbranched alkyl optionally partially or
fully halogenated and alkylamino;
25
or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring;
m = 0, 1 or 2;
30 X = O or S; and
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the pharmaceutically acceptable derivatives thereof.
2. The compound according to claim 1 wherein
Gis:
phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl,
benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl, benzofuran-3-one, 4H-
benzo[ 1 ? 4]oxazine-3-one;
pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl,
tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl,
benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl,
dihydrobenzothiophenyl, benzooxazolonyl, benzo[l,4]oxazin-3-onyl, benzodioxolyl 5
benzo[l,3]dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl,
indolinonyl, phthalimidyl;
oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl,
morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene
sulfoxidyl, oxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl,
pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl,
thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl,
thioxanyl or dithianyl;
wherein G is substituted by one or more Ri, R2 or R3.
3. The compound according to claim 2 wherein
G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl,
benzimidazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl,
dihydrobenzofuranyl, dihydrobenzothiophenyl, indanyl, indenyl, indolyl, indolinyl,
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indolonyl,indolinonyl, benzofuran-3-one or 4H-benzo[l,4]oxazine-3-one, wherein G is
substituted by one or more Ri, R2 or R3;
Ar is:
5
naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl,
tetrahydroiso quinolinyl, indanyl, indenyl or indolyl each optionally substituted by one or
more R4 or R5 groups;
10 L is a:
C1-4 saturated or unsaturated branched or unbranched carbon chain;
wherein one or more methylene groups are optionally independently replaced by
heteroatoms chosen from O, N and S(0) m ; and
15 wherein said L is optionally substituted with 0-2 oxo groups and one or more C1-4
branched or unbranched alkyl optionally substituted by one or more halogen atoms;
Qis:
20 phenyl, naphthyl, pyridinyl or imidazolyl which are optionally substituted with one to
three halogen, C1.3 alkyl, C1-3 alkoxy, hydroxy, amino, mono- or di-(Ci_3 alkyl)amino or
mono- or di-(phenyl-Ci_3 alkyl)amino;
tetrahydropyranyl, tetrahydrofuranyl, morpholino, thiomorpholino, thiomorpholino
25 sulfoxide, piperidinyl, piperidinonyl, tetrahydropyrimidonyl, pentamethylene sulfide,
pentamethylene sulfoxide or pentamethylene sulfone which are optionally substituted
with one to three C1.3 alkyl, C1.3 alkoxy, hydroxy, mono- or di-(Ci_3 alkyl)amino-Ci_3
alkyl, phenylamino-Ci-3 alkyl or Ci_ 3 alkoxy-Ci-3 alkyl;
30 each Ri is independently:
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C3.5 branched or unbranched alkyl optionally partially or fully halogenated, and
optionally substituted with one to three C3-6 cycloalkyl, hydroxy, phenyl, thienyl, furyl,
isoxazolyl or isothiazolyl; each of the aformentioned being optionally substituted with 1
to 5 halogen, C1-3 alkyl which is optionally partially or fully halogenated, hydroxy, cyano
or C 1.3 alkoxy optionally partially or fully halogenated;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl
optionally partially or fully halogenated and optionally be substituted with one to three
C1-3 alkyl groups optionally partially or fully halogenated, cyano, hydroxy Ci^alkyl or
phenyl; or an analog of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl,
bicyclopentanyl or bicyclohexanyl wherein one to three ring methylene groups are
independently replaced by O, S, CHOH, >C=0, >C=S or NH; or
silyl containing three C1-4 independently branched or unbranched alkyl groups optionally
partially or fully halogenated;
each R3 is independently:
hydrogen, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrrolylidinyl, imidazolyl
or pyrazolyl, wherein each of the aforementioned is optionally substituted with one to
five phenyl, naphthyl, heterocycle or heteroaryl as hereinabove described in this
paragraph, Ci_6 branched or unbranched alkyl optionally partially or fully halogenated,
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl,
bicyclohexanyl, bicycloheptanyl, phenyl C1-5 alkyl, naphthyl C1.5 alkyl, halogen, oxo,
hydroxy, cyano, C1-3 alkoxy optionally be partially or fully halogenated, phenyloxy,
naphthyloxy, heteraryloxy or heteryclicoxy wherein the heteraryl or heterocyclic moiety
is as hereinabove described in this paragraph, nitro, amino, mono- or di-(Ci^)alkylamino,
phenylamino, naphthylamino, heterocyclic or heteroaryl amino wherein the heterocyclic
or heteroaryl moiety is as hereinabove described in this paragraph, NH2C(0), a mono- or
di-(Ci_3)alkyl aminocarbonyl, C1.5 alkyl-C(0)-Ci_4 alkyl, amino-Ci-5 alkyl, mono- or di-
(Ci-3)alkylamino-Ci_5 alkyl, amino-S(0)2, di-(Cio)alkylamino-S(0)2, R/rQ-s alkyl, Rs-
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15
Ci_5 alkoxy, R$rC(0)-Ci_5 alkyl, R10-C1.5 alkyl(Rn)N or carboxy-mono- or di-(Ci-s)-
alkyl-amino;
C1-3 alkyl or C1-3 alkoxy optionally partially or fully halogenated or optionally substituted
5 with Rn;
Cyclopropyloxy, cyclopentyloxy or cyclohexyloxy which are optionally partially or fully
halogenated and optionally substituted with one to three C1-3 alkyl groups optionally
partially or fully halogenated, wherein one to three ring methylene groups are replaced
10 independently by O, S(0) m , CHOH, >00, >OS or NH;
Co-6 branched or unbranched alkyl optionally substituted with ORis;
amino or C1-C5 branched or unbranched mono- or di-alkylamino optionally substituted
with R19;
R 20 C(O)N(R 21 )-, R22O- ; R 23 R 24 NC(0)-; R 26 CH 2 C(0)N(R 2 i)- or R 26 C(0)CH 2 N(R 21 )-;
C 2 _4 alkenyl substituted by R 2 3R 2 4NC(0)-;
20 C 2 -4 alkynyl branched or unbranched carbon chain optionally partially or fully
halogenated and optionally independently substituted with 0-2 oxo groups, pyrroldinyl,
pyrrolyl or one or more C1-4 branched or unbranched alkyl optionally substituted by one
or more halogen atoms;
25 X is O;
and
R 2 3 and R 2 4 taken together optionally form imidazole, piperidine, morpholino, piperazine
or a pyridinyl ring.
30
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4. The compound according to claim 3 wherein:
G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl,
benzothiophenyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indanyl, indolyl,
indolinyl, indolonyl, indolinonyl, cyclopropanyl, cyclohexanyl, piperidinyl or
tetrahydropyran, wherein G is substituted by one or more Ri, R2 or R3;
Ar is naphthyl;
L is a:
C1-4 alkyl or alkynyl branched or unbranched carbon chain;
wherein one methylene group is optionally independently replaced by
heteroatoms chosen from O, S(0) m and N; and
wherein said L is optionally substituted with 0-2 oxo groups and one or more C1-2
alkyl optionally substituted by one or more halogen atoms;
Qis:
phenyl, pyridinyl, pyrimidinyl, imidazolyl, tetrahydropyranyl, morpholino,
thiomorpholino, thiomorpholino sulfoxide, piperidinyl, piperidinonyl or pentamethylene
sulfoxide which are optionally substituted with one to three, amino, mono- or di-(phenyl-
C1-3 alkyl)amino, methyl, ethyl, methoxy, ethoxy, methoxymethyl or ethoxymethyl;
each Ri is independently:
C3-5 branched or unbranched alkyl, optionally partially or fully halogenated, and
optionally substituted with phenyl substituted with 0 to 5 halogen, C1-3 alkyl optionally
partially or fully halogenated, hydroxy, cyano or Ci^alkoxy optionally partially or fully
halogenated;
74
WO 01/36403
PCT/US00/31582
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl
optionally partially or fully halogenated and optionally substituted with one to three C1-3
alkyl groups optionally partially or fully halogenated, CYANO, hydroxyCi_3alkyl or
phenyl; or an analog of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl,
bicyclopentanyl or bicyclohexanyl wherein one ring methylene group is replaced by O;
and
silyl containing three Ci_ 2 independently branched or unbranched alkyl groups optionally
partially or fully halogenated;
each R3 is independently:
hydrogen, phenyl , pyridinyl, pyrimidinyl, pyrrolylidinyl, 2,5-pyrrolidin-dione,
imidazolyl, pyrazolyl, each of the aforementioned is optionally substituted with one to
five C1-3 alkyl optionally partially or fully halogenated, halogen, oxo, hydroxy, cyano or
Ci_3 alkoxy optionally partially or fully halogenated;
C1-3 alkyl or C 1-3 alkoxy optionally partially or fully halogenated or optionally substituted
with R17;
Cyclopropyloxy, cyclopentyloxy or cyclohexyloxy which are optionally partially or fully
halogenated and optionally substituted with one to three C1.3 alkyl groups optionally
partially or fully halogenated, wherein one to three ring methylene groups are replaced
independently by O, S(0) m , CHOH, >00, >C=S or NH;
C0-3 branched or unbranched alkyl optionally substituted with ORig;
amino or C1-C3 branched or unbranched mono- or di-alkylamino optionally substituted
with R19;
R 2 oC(0)N(R 2 i)-, R22O- ; R 23 R 24 NC(0)-; R 26 CH 2 C(0)N(R 21 )- or R 26 C(0)CH 2 N(R 21 )-;
75
WO 01/36403
PCT/US00/31582
C2-4 alkenyl substituted by R23R24NC(0)-; or
C2-4 alkynyl substituted with pyrroldinyl or pyrrolyl;
and
R23 and R24 taken together optionally form morpholino.
5. The compound according to claim 4 wherein:
G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl,
dihydrobenzofuranyl, indanyl, indolinyl, indolonyl, indolinonyl or cyclopropanyl,
wherein G is substituted by one or more Ri, R2 or R3;
Ar is 1 -naphthyl;
L is a: O-CH2-, 0-CH 2 CH 2 , 0-CH 2 CH 2 CH 2? 0-CH 2 CH 2 (CH 3 ), 0-CH 2 (CH 3 )CH 2 ,
NHCH 2 , NHCH 2 CH 2 ,NHCH 2 CH 2 CH 2 , S(0) m CH 2 , S(0) m CH 2 CH 2 , S(0) m CH 2 CH 2 CH 2 ,
CH 2 CH 25 CH 2 CH 2 CH 2 , 0-CH 2 C(0),
HC=C— CH 2 or HC=C— CH 2 0
each Ri is independently:
C3.5 branched or unbranched alkyl optionally partially or fully halogenated, and
optionally substituted with phenyl;
cyclopropyl, cyclopentanyl, cyclohexanyl or bicyclopentanyl optionally substituted with
one to three methyl groups optionally partially or fully halogenated, CYANO,
hydroxy methyl or phenyl;
cyclopentyloxy or cyclohexyloxy which are optionally partially or fully halogenated;
2-tetrahydrofuranyl substituted by methyl; or
trimethylsilyl;
76
WO 01/36403
PCT/US00/31582
each R3 is independently:
hydrogen, phenyl, pyridinyl, pyrimidinyl, pyrrolylidinyl, 2,5-pyrrolidin-dione,
5 imidazolyl or pyrazolyl, wherein each of the aforementioned is optionally substituted
with Ci_2 alkyl optionally partially or fully halogenated;
C1-3 alkyl or C1.3 alkoxy each optionally be partially or fully halogenated or optionally
substituted with diethylamino;
10
C0-3 branched or unbranched alkyl optionally substituted with ORis;
amino or C1-C3 branched or unbranched mono- or di-alkylamino optionally substituted
with R19;
15 CH 3 C(0)NH-, R22O- ; R 23 R 2 4NC(0)-; R 26 CH 2 C(0)N(R 2 i)- or R 26 C(0)CH 2 N(R 21 )-;
C 2 -4 alkenyl substituted by R 2 3R 2 4NC(0)-; or
C 2 _4 alkynyl substituted with pyrroldinyl or pyrrolyl;
20 R 2 3 and R 2 4 are H or R 2 3 and R 2 4 taken together optionally form morpholino; and
R 2 6 is morpholino.
25 6. The compound according to claim 5 wherein
G is phenyl substituted by one or more Ri, R 2 or R3;
and
L is:
30 O, NH, CH 2 or S(0) m .
7. The compound according to claim 4 wherein
77
WO 01/36403 PCT/US00/31582
G is phenyl or pyridinyl substituted by one or more Ri, R2 or R 3 ;
Ar is 1-naphthyl;
L is:
C(0)CH 2 - , >C(0), O, or CH 2 ;
each Ri is independently;
C3_5 branched or unbranched alkyl optionally partially or fully halogenated, and
each R3 is independently:
hydrogen, C1.3 alkyl or C 1-3 alkoxy each optionally be partially or fully halogenated or
optionally substituted with diethylamino;
CH 3 C(0)NH-, R22O- ; R 23 R24NC(0)-; R 26 C(0)N(R 21 )- or R 26 C(0)CH 2 N(R 2i )-;
R 2 3 and R 2 4 are H or R 2 3 and R24 taken together optionally form morpholino;
and
R 2 6 is alkylamino mono- or di-Co-4 branched or unbranched.
8. The compound according to claim 7 wherein
G is pyridinyl
and
L is C(Q)CH 2 - , >C(Q), O or CH 2 ,
9. A compound selected from:
1 -(5-tert-Butyl-2-methoxyphenyl)-3-[4-(2-methoxy-pyridin-4-yl-oxy)-naphthalen- 1 -yl]
urea;
78
WO 01/36403 PCT/US00/31582
1 -(5-teit-Butyl-2-methoxyphenyl)-3-[4-(2-m 1 -yl]-
urea;
1 -(5-tert-Bulyl-2 5 3-dimethoxyphenyl)-3-[4-(2-methoxy-pyridin-4-yl-oxy)-n^ 1 -
yl]-urea;
5-tert-Butyl-2-methoxy-3- {3-[-(pyridin-4-yl-oxy)naphthalen- 1 -yl]ureido} benzamide;
Morpholine-4-carboxylic acid (5-tert-butyl-2-methoxy-3- {3-[-(pyridin-4-yl-
oxy)naphthalen- 1 -yl]ureido}phenyl)amide;
N-(5-tert-Butyl-2-methoxy-3- {3-[-(pyridin-4-yl-oxy)naphthalen- 1 -
yl]ureido} phenyl)acetamide;
3-(5-tert-Butyl-2-methoxy-3- {3-[-(pyridin-4-yl-oxy)naphthalen- 1 -yl]ureido}phenyl)-
1 , 1 -dimethylurea;
1 -[4-(2-Amino-pyridin-4-yloxy)-naphthalen- 1 -yl]-3-(5-tert-butyl-2 ? 3-dimethoxy-
phenyl)-urea;
l-(5-tert-Butyl-23-dimethoxy-phenyl)-3-[4-(2-methylamino-pyridin-4-ylox
naphthalen- 1 -yl]-urea;
1 -(5-tert-Butyl-2,3-dimethoxy-phenyl)-3- {4-[2-( 1 -phenyl-ethylamino)-pyridin-4-
yloxy] -naphthalen- 1 -yl} -urea;
1 -[4-(2-Amino-pyridin-4-yloxy)-naphthalen- 1 -yl]-3-(5-tert-butyl-2-methoxy-pyridin-3-
yl)-urea;
l-(5-tert-Butyl-2-methoxy-pyridin-3-yl)-3-[4-(2-methylamino-pyridin-4-yloxy)-
naphthalen- 1 -yl] -urea;
l-(5-tert-Butyl-2-methoxy-pyridin-3-yl)-3-{4-[2-(l-phenyl-ethylamino)-pyridin-4-
y loxy] -naphthalen- 1 -y 1 } -urea;
1 -(5-tert-Butyl-2-methylphenyl)-3-[4-(2-aminopyridin-4-yl-oxy)naphthalen- 1 -yljurea;
1 -(5-tert-Butyl-2-morpholin-4-y^
yl]-urea;
79
WO 01/36403 PCT/US00/31582
l-[3-Bromo-5-tert-butyl-2-(2-morpholin-4-yl-ethylamino)-phenyl]-3-
y l-ethoxy)-naphthalen- 1 -y 1] -urea;
l-[5-tert-bulyl-2-methoxyphenyl]-3-[4-(2-(2-phenoxymethyl)morpholin-^
naphthalen- 1 -yl]-urea;
l-[5-tert-butyl-2-methylphenyl]-3-[4-(2-moipholin-4-yl-ethoxy)-naphthalen
1 -[5-tert-butyl-2-methylphenyl]-3-[4-(4-pyridinyloxy)-naphthalen- 1 -yl]-urea;
1 -[5-tert-butyl-2-methylphenyl]-3-[4-(3-pyridinyloxy)-naphthalen- 1 -yl]-urea.
and the pharmaceutical^ acceptable salts thereof.
10. The compound according to claim 7 wherein the compound is selected from:
1 -(5-tert-Butyl-2-methylphenyl)-3-[4-(2-aminopyridin-4-yl-oxy)naphthalen- 1 -yl]urea;
1 -(5 -tert-Butyl-2-morpholin-4-y 1-pheny l)-3 - [4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -
yl]-urea,
l-[3-Bromo-5-tert-butyl-2-(2-morpholin-4-yl-ethylamino)-phenyl]-3-[4-(2-morpholin-4-
yl-ethoxy)-naphthalen- 1 -yl]-urea,
l-[5-tert-butyl-2-methoxyphenyl]-3-[4-(2-(2-phenoxymethyl)morpholin-4-yl-ethoxy)-
naphthalen- 1 -yl]-urea,
1 -[5-tert-butyl-2-methylphenyl]-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-urea,
l-[5-tert-butyl-2-methylphenyl]-3-[4-(4-pyridinyloxy)-naphthalen-l-yl]-urea;
1 -[5-tert-butyl-2-methylphenyl]-3-[4-(3-pyridinyloxy)-naphthalen- 1 -yl]-urea
and the pharmaceutically acceptable salts thereof.
80
WO 01/36403
PCT/US00/31582
11. A pharmaceutical composition comprising a pharmaceutical^ effective amount of a
compound according to claims 1 or 9.
12. A method of treating a disease mediated by cytokines which comprises administering
to a patient in need of such treatment a therapeutically effective amount of a compound
according to claim 1 or 9.
13. The method according to claim 12 wherein the cytokine-mediated disease is selected
from rheumatoid arthritis, osteoarthritis, Crohn's disease, ulcerative colitis, multiple
sclerosis, Guillain-Barre syndrome, psoriasis, graft versus host disease, systemic lupus
erythematosus, diabetes, toxic shock syndrome, osteoporosis, Alzheimer's disease, acute
and chronic pain, contact dermatitis and atherosclerosis.
14. A method of treating a neutrophil-mediated disease selected from stroke, myocardial
infarction, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ
injury secondary to trauma, acute glomerulonephritis, dermatoses with acute
inflammatory components, acute purulent meningitis, hemodialysis, leukopherisis,
granulocyte transfusion associated syndromes and necrotizing entrerocolitis, which
comprises administering to a patient in need of such treatment a therapeutically effective
amount of a compound according to claim 1 or 9.
15. A method of making a compound of the formula(I):
81
WO 01/36403
PCT7US00/31582
X
J<^ ^Ar — L O
I I
H H CD;
wherein X is O and G, Ar, L and Q are as defined in claim 1 ,
said method comprising:
a) reacting an arylamine with phenyl chloroformate in a suitable solvent with a suitable
base at 0 - 85°C for 2-24 hours:
cico 2 p h a M JL.Ph
NH 2 - N O
H
b) reacting the product of step a) with an arylamine shown below in a non-protic
anhydrous at 0 — 1 10°C for 2-24 hours, to produce a compound of the formula (I):
O
G_A^Ph
Q-L-Ar-NH
N
i
H
O
X
Jk. „Ar
N N
I I
H H
(I)
82
Interns
Application No
PCT/US
00/31582
A. CLASSIFICATION OF SUBJECT MATTER
IPC 7 C07D295/08 A61P29/00
C07D213/73 C07D295/12 C07D213/63
According to International Patent Classification (IPC) or to both national classification and IPC
B. FIELDS SEARCHED
Minimum documentation searched (classification system followed by classification symbols)
IPC 7 C07D
Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
Electronic data base consulted during the international search (name of data base and, where practical, search terms used)
EPO-Internal , WPI Data, PAJ
C. DOCUMENTS CONSIDERED TO BE RELEVANT
Category °
Citation of document, with indication, where appropriate, of the relevant passages
Relevant to claim No.
P,x
p,x
WO 00 55139 A (BOEHRINGER INGELHEIM
PHARMA) 21 September 2000 (2000-09-21)
claim 1; examples 18,19,38
W0 00 55152 A (BOEHRINGER INGELHEIM
PHARMA) 21 September 2000 (2000-09-21)
claim 1
W0 99 23091 A (BOEHRINGER INGELHEIM
PHARMA) 14 May 1999 (1999-05-14)
cited in the application
claim 1
1-15
1-15
1-15
US 5 162 360 A (CRESWELL MARK W
10 November 1992 (1992-11-10)
cited in the application
claim 1
ET AL)
1-5
-/—
m
Further documents are listed in the continuation of box c.
Patent family members are listed in annex.
Special categories of cited documents
"A"
lip'B
II ^11
document defining the genera! state of the art which is not
considered to be of particular relevance
earlier document but published on or after the international
filing date
document which may throw doubts on priority claim{s) or
which is cited to establish the publication date of another
citation or other special reason (as specified)
"O" document referring to an oral disclosure, use, exhibition or
other means
"P" document published prior to the international filing date but
later than the priority date claimed
"T" later document published after the international filing date
or priority date and not in conflict with the application but
cited to understand the principle or theory underlying the
invention
"X" document of particular relevance; the claimed invention
cannot be considered novel or cannot be considered to
involve an inventive step when the document is taken alone
"Y B document of particular relevance; the claimed invention
cannot be considered to involve an inventive step when the
document is combined with one or more other such docu-
ments, such combination being obvious to a person skilled
in the art.
document member of the same patent family
Date of the actual completion of the international search
28 February 2001
Date of mailing of the international search report
29.03.01
Name and mailing address of the ISA
European Patent Office, P.B. 5818 Patentlaan 2
NL - 2280 HV Rijswijk
Tel. (+31-70) 340-2040, Tx. 31 651 epo nl,
Fax: (+31-70) 340-3016
Authorized officer
Gettins, M
Form PCT/ISA/210 (second sheet) (July 1992)
INTERNATIONAL SEARCH REPORT
Interna I Application No
PCT/US 00/31582
C.(Continuation) DOCUMENTS CONSIDERED TO BE RELEVANT
Category
Citation of document, with indication.where appropriate, of the relevant passages
Relevant to claim No.
WO 98 52558 A (CHEN JINSHAN ; PAULSEN
HOLGER (DE); RANGES GERALD (US); RENICK
JOEL) 26 November 1998 (1998-11-26)
cited in the application
claim 1
WO 96 25157 A (HERTZBERG ROBERT PHILIP
;JUREWICZ ANTHONY JOSEPH (US); RUTLEDGE
ME) 22 August 1996 (1996-08-22)
claim 1
WO 99 32111 A (BAYER AG)
1 July 1999 (1999-07-01)
claim 1
W0 99 32110 A (BAYER AG)
1 July 1999 (1999-07-01)
claim 1
W0 99 32106 A (BAYER AG)
1 July 1999 (1999-07-01)
claim 1
W0 99 32463 A (BAYER AG)
1 July 1999 (1999-07-01)
claim 1
1-15
1-15
1-15
1-15
1-5
1-15
US 4 423 126 A (KLIJAN0WICZ JAMES E
AL) 27 December 1983 (1983-12-27)
claim 1
ET
1-10
Form PCTYISA/210 (continuation ot second sheet) (July 1992)
INTERNATIONAL SEARCH REPORT
International application No.
PCT/US 00/31582
Box I Observations where certain claims were found unsearchable (Continuation of item 1 of first sheet)
This International Search Report has not been established in respect of certain claims under Article 17(2){a) for the following reasons:
1.
2.
Claims Nos.:
because they relate to subject matter not required to be searched by this Authority, namely:
Although claims 12-14 are directed to a method of treatment of the
human/animal body, the search has been carried out and based on the alleged
effects of the compound/composition.
Claims Nos.: ~"
because they relate to parts of the International Application that do not comply with the prescribed requirements to such
an extent that no meaningful International Search can be carried out, specifically:
see FURTHER INFORMATION sheet PCT/ISA/210
3. | | Claims Nos.:
because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a).
Box II Observations where unity of invention is lacking (Continuation of item 2 of first sheet)
This International Searching Authority found multiple inventions in this international application, as follows:
As all required additional search fees were timely paid by the applicant, this International Search Report covers all
searchable claims.
2.
As all searchable claims could be searched without effort justifying an additional fee, this Authority did not invite payment
of any additional fee.
As only some of the required additional search fees were timely paid by the applicant, this International Search Report
covers only those claims for which fees were paid, specifically claims Nos.:
No required additional search fees were timely paid by the applicant. Consequently, this International Search Report is
restricted to the invention first mentioned in the claims; it is covered by claims Nos.:
Remark on Protest
The additional search fees were accompanied by the applicant's protest.
No protest accompanied the payment of additional search fees.
Form PCT/ISA/210 (continuation of first sheet (1)) (July 1998)
INTERNATIONAL SEARCH REPORT
International Application No. PCTAJS 00 #1582
FURTHER INFORMATION CONTINUED FROM PCT/ISA/ 210
Continuation of Box 1.2
Present claims 1-15 relate to an extremely large number of possible
compounds. Support within the meaning of Article 6 PCT and/or disclosure
within the meaning of Article 5 PCT is to be found, however, for only a
very small proportion of the compounds/methods claimed. In the present
case, the claims so lack support, and the application so lacks
disclosure, that a meaningful search over the whole of the claimed scope
is impossible. Consequently, the search has been carried out for those
parts of the claims which appear to be supported and disclosed, namely
those parts relating to the compounds of formula (I) where Ar is
1-naphthyl and G is phenyl or pyridyl. This covers all of the compounds
which are specifically claimed and/or have been tested. . Claims 6-10 can
be considered to have been fully searched.
The applicant's attention is drawn to the fact that claims, or parts of
claims, relating to inventions in respect of which no international
search report has been established need not be the subject of an
international preliminary examination (Rule 66.1(e) PCT). The applicant
is advised that the EPO policy when acting as an International
Preliminary Examining Authority is normally not to carry out a
preliminary examination on matter which has not been searched. This is
the case irrespective of whether or not the claims are amended following
receipt of the search report or during any Chapter II procedure.
INTERNATIONAL SEARCH REPORT
Information on patent family members
Intern I Application No
PCT/US 00/31582
Patent document
cited in search report
Publication
date
Patent family
member(s)
Publication
date
WO 0055139
21-09-2000
AU
2881700 A
04-10-2000
wo
0055152
A
21-
-09-
2000
NONE
wo
9923091
A
14-
-05-
1999
AU
1367599
A
24-05-1999
EP
1028953
A
23-08-2000
US
5162360
A
n
10-
X V/
-11-
X X
■1992
NONE
WO
9852558
A
26-
-11-
1998
AU
7585498
A
11-12-1998
DE
1019040
T
■
08-02-2001
EP
1019040
A
19-07-2000
ES
2151467
T
01-01-2001
wo
9625157
A
22-
-08-
1996
EP
0809492
A
03-12-1997
JP
11503110
T
23-03-1999
NO
983737
A
14-10-1998
US
5886044
A
n
23-03-1999
us
5780483
A
14-07-1998
9932111
A
n
01-
-07-
1999
AU
1997199
X J 7 / X 7 7
A
n
12-07-1999
EP
1041982
A
11-10-2000
WO
9932110
A
01
-07-
■1999
AU
1997099
A
12-07-1999
EP
1043995
A
18-10-2000
wo
9932106
A
01
-07-
1999
AU
2198999
A
12-07-1999
EP
1047418
A
02-11-2000
NO
20003232
A
21-08-2000
WO
9932463
A
01
-07-
1999
AU
1939999
A
12-07-1999
EP
1042305
A
11-10-2000
us
4423126
A
27
-12-
1983
CA
1206972
A
01-07-1986
DE
3365436
D
25-09-1986
EP
0095899
A
07-12-1983
JP
58215460
A
14-12-1983
US
4536598
A
20-08-1985
Form PCT/ISA/210 (patent family annex) (July 1992)
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